Alpha-amino,-thio,-oxo substituted ketones as phospholipase inhibitors

ABSTRACT

Inhibitors of the cytosolic phospholypase A2 enzymes are provided which are of use in controlling a wide variety of inflammatory diseases. The inhibitors of the present invention have the general formula 
                 
 
wherein X, Z, X 1 , R 1 , R 2 , R a , R b , R 3 , R 4  and Y are as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 60/203,741 filed May 11, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to certain alpha amino, thio, oxosubstituted ketone compounds, their salts, hydrates and derivativesthereof, a process for their preparation, intermediates useful in theirpreparation, and pharmaceutical compositions containing them. Suchketone compounds are inhibitors of phospholipase A2 enzymes that areinvolved in the human inflammatory diseases and are thus useful agentsin the treatment of inflammatory diseases such as asthma, arthritis,inflammatory bowel disease, and neurodegenerative diseases.

2. Background of the Invention and Description of the Prior Art

Inflammatory diseases of the skin, such as psoriasis and atopicdermatitis, afflict greater than 5% of the population. Inflammatorydiseases such as asthma affect more than 10 million people in U.S.alone. Currently the treatment of these disorders typically involves thetopical and inhalation use of coricosteroids and broncodilators.However, these agents also have undesirable side effects such as skinatrophy which limit the duration of therapy. In addition, topicalapplication of a drug is difficult for many patients where the affectedarea may be very large.

Phospholipase A₂ (PLA₂) is the common name for phosphatide2-acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl esterbond of phosphoglycerides and results in production of lysophospholipidsand free fatty acids. When the fatty acid is arachidonic acid, furtheraction by cyclooxygenase and 5-lipoxygenase enzymes results ineicosanoid production, which is implicated in inflammation andleukotrienes which are linked to asthma. Lysophophospholipid metabolismresults in production of platelet activating factor and bothlysophospholipids and platelet activating factor play a role ininflammation.

PLA₂ enzymes exist as secreted forms (MW˜12,000-15,000) and cytosolicforms (MW˜85,000). The cytosolic or cPLA₂ enzymes appear to play a keyrole in the pathway leading to the formation of platelet activatingfactor and the eicosanoids.

Inappropriate activation of the cytosolic PLA₂ enzymes, therefore, canresult in a variety of chronic and acute conditions including asthma,cerebral ischemia (Clemens et al, Stroke, 1996, 27, 527-535),Alzheimer's Disease (Stephenson et al, Neurobiology of Stroke, 1996, 3,51-63 and see also U.S. Pat. No. 5,478,857), rheumatoid arthritis,neutrophil and platelet activation (Huang et al, Mediators ofInflammation, 1994, 3, 307-308), chronic skin inflammation and damage tothe skin resulting from exposure to ultraviolet light (Gresham, et al.,American Journal of Physiology, 1996, 270; Cell Physiology39:C1037-C1050) and macrophage activation (Balsinde, et al., Journal ofBiological Chemistry, 1996, 271, 6758-6765).

Inhibitors of the cPLA₂ enzymes may, therefore, be of use in controllinga wide variety of inflammatory diseases. The literature describes asignificant number of compounds said to be phospholipase A₂ inhibitors.

Biochemistry (1993) 32: 5935-5940, discloses a trifluoromethyl ketoneanalog of arachidonic acid having the formula

as a selective inhibitor of cPLA₂.

Bioorganic Med. Chem. Lett. (1995) 5: 519-522, discloses selective cPLA₂inhibitors of the formula

where R is either H or OH.

Japanese published Patent Application JP09268153A (Derwent No.97-554679/51) discloses cPLA₂ inhibitors of the formula RCOCF₃ where RCOis an acyl residue of an n-3 series highly unsaturated fatty acid. Thecompounds are said to be useful as antiinflammatory or anti-allergicdrugs.

Certain trifluoromethylketone have been disclosed as inhibitors of fattyacid amide hydrolase in Bioorg. & Med. Chem. Lett. (1999) 9, 265-270.

Published PCT Application WO 98/25893 discloses arylsulfonamidecompounds of the general formula

wherein

-   -   A represents a C₄-C₁₀ alkyl group, an aryl group, an arylalkyl        group, radicals selected from the group consisting of —CH═CH—B,        —O—B, —S—B, and —NH—B, or radicals of formula —CH₂—X,        wherein    -   B represents a non-aromatic C₃-C₈ carbocycle, a C₃-C₈ alkyl        group, a heterocycle or an arylalkyl group, each of which is        optionally substituted with one or more members independently        selected from the group consisting of a halogen atom, a C₁-C₄        alkyl group, a C₁-C₄ alkoxy group, cyano, nitro, a heterocycle,        an aryl group and an aryloxy group, and    -   X is a member selected from the group consisting of a halogen        atom, —S-aryl, —S-heterocycle, and —PO₃R₂ wherein each R is        independently selected from the group consisting of a hydrogen        atom and C₁-C₃ alkyl;    -   R¹ and R² each independently represent a hydrogen atom, a lower        alkyl group, or a group represented by the formula:        —(CH₂)_(q)—A′ wherein q is an integer of 2 to 4, and A′ is a        member selected from the group consisting of a hydroxyl group, a        group represented by the formula:    -   wherein R⁵ and R⁶ each independently represent a hydrogen atom,        a lower alkyl group, or a group represented by the formula:    -   wherein R⁷ represents a hydrogen atom, a lower alkyl group, or a        group represented by the formula:    -   wherein s is an integer of 2 to 5; or    -   R¹ and R² each independently represent an unsubstituted        cycloalkyl group, or a cycloalkyl substituted with a lower alkyl        or halogen or condensed with an aromatic ring, a bicycloalkyl,        or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an        aliphatic saturated hydrocarbon group made of two or three        rings, respectively, with at least two carbon atoms being common        to each ring, or an azabicycloalkyl group which is a        bicycloalkyl group as described above in which one carbon atom        is replaced by a nitrogen atom or a group represented by the        formula:    -   wherein g and h are each an integer of 1 to 4, and B′ stands for        a lower alkyl group, an arylalkyl group, an arylalkyl group        substituted by lower alkyl; halogen or a lower alkoxy group, or        a pyridylalkyl group, or a pyridylalkyl group substituted with a        lower alkyl group, a halogen or a lower alkoxy group; or    -   R¹ and R² may be combined together to form a 6- or 7-membered        ring which may contain a nitrogen or oxygen atom in addition to        the nitrogen atom to which R¹ and R² are bonded, and said 6- or        7-membered ring may be substituted with a lower alkyl,        arylalkyl, cycloalkylalkyl or heteroarylalkyl group;    -   R³ represents a hydrogen atom, a lower alkyl group, or a C₃-C₈        cycloalkyl group;    -   R⁴ represents a hydrogen atom, a lower alkyl group, a lower        alkoxy group or a halogen atom;    -   n is an integer of 1 to 4, provided that when n is 2, the two R⁴        groups may form a cyclohexenyl or phenyl ring together with two        adjacent carbon atoms constituting the benzene ring; and any        pharmacologically acceptable salts thereof as inhibitors of        phospholipase A₂ activity, particularly cPLA₂.

The published PCT Application WO 98/08818 discloses Inhibitors ofphospholipase enzymes of formulae I, II and III.

or a pharmaceutically acceptable salt thereof, wherein:

-   -   A is independent of any other group and is selected from the        group consisting of —CH₂— and —CH₂—CH₂—;    -   B is independent of any other group and is selected from the        group consisting of —(CH₂)_(n)—, —(CH₂O)_(n)—, —(CH₂S)_(n)—,        —(OCH₂)_(n)—, —(SCH₂)_(n)—, —(CH═CH)_(n)—, —(C≡C)_(n)—,        —CON(R₆)—, —N(R₆)CO—, —O—, —S— and —N(R₆)—;    -   R₁ is independent of any other R group and is selected from the        group consisting of —X—R₆, —H, —OH—, halogen, —CN, —NO₂, C₁-C₅        alkyl, alkenyl, alkynyl, aryl and substituted aryl;    -   R₂ is independent of any other R group and is selected from the        group consisting of —H, —COOH, —COR₅, —CONR₅R₆,        —(CH₂)_(n)—W—(CH₂)_(m)—Z—R₅, —(CH₂)_(n)—W—R₅, —Z—R₅, C₁-C₁₀        alkyl, alkenyl and substituted aryl;    -   R₃ is independent of any other R group and is selected from the        group consisting of —H, —COOH, —COR₅, —CON R₅R₆,        —(CH₂)_(n)—W—(CH₂)_(m)—Z—R₅, —(CH₂)_(n)—W—R₅, —Z—R₅, C₁-C₁₀        alkyl, alkenyl and substituted aryl;    -   R₄ is independent of any other R group and is selected from the        group consisting of —H, —OH, OR₆, SR₆, CN, —COR₆, —NHR₆, —COOH,        —CONR₆R₇, —NO₂, —CONHSO₂R₈, C₁-C₅ alkyl, alkenyl and substituted        aryl;    -   R₅ is independent of any other R group and is selected from the        group consisting of —H, —OH, —O(CH₂)_(n)R₆, —SR₆, —CN, —COR₆,        —NHR₆, —COOH, —NO₂, —COOH, —CONR₆R₇, —CONHSO₂R₈, C₁-C₅ alkyl,        alkenyl, alkynyl, aryl, substituted aryl, —CF₃, —CF₂CF₃ and    -   R₆ is independent of any other R group and is selected from the        group consisting of —H, C₁-C₅ alkyl, alkenyl, alkynyl, aryl and        substituted aryl;    -   R₇ is independent of any other R group and is selected from the        group consisting of —H, C₁-C₅ alkyl, alkenyl, alkynyl, aryl and        substituted aryl;    -   R₈ is independent of any other R group and is selected from the        group consisting of C₁-C₃ alkyl, aryl and substituted aryl;    -   R₉ is independent of any other R group and is selected from the        group consisting of —H, —OH, a halogen, —CN, —OR₆, —COOH,        —CONR₆R₇, tetrazole, —CONHSO₂R₈, —COR₆, —(CH₂)_(n)CH(OH)R₆ and        —(CH₂)_(n)CHR₆R₅;    -   R₁₀ is independent of any other R group and is selected from the        group consisting of —H, —OH, a halogen, —CN, —OR₆, —COOH,        —CONR₆R₇, tetrazole, —CONHSO₂R₈, —COR₆, —(CH₂)_(n)CH(OH)R₆ and        —(CH₂)_(n)CHR₆R₅;    -   W is, independent each time used including within the same        compound, selected from the group consisting of —O—, —S—, —CH₂—,        —CH═CH—, —C≡C— and —N(R₆)—;    -   X is independent of any other group and is, independently each        time used including within the same compound, selected from the        group consisting of —O—, —S— and —N(R₆)—;    -   Z is independent of any other group and is, independently each        time used including within the same compound, selected from the        group consisting of —CH₂—, —O—, —S—, —N(R₆)—, —CO—, —CON(R₆)—        and —N(R₆)CO—;    -   m is, independently each time used including within the same        compound, an integer from 0 to 4; and    -   n is independently of m and is, independently each time used        including within the same compound, an integer from 0 to 4.

Drugs 1998, Vol. 1, No. 1, pp. 49-50 discloses a limited series of cPLA₂inhibitors as shown below

R₁ R₂ X CH₃ (1) (1) (1) CH₃(CH₂)₉— CH₃(CH₂)₉— Ph(CH₂)_(5 CH) ₃(CH₂)₉— OO S SO₂

U.S. Pat. No. 5,866,318 relates to methods for inhibiting cell death inmammalian cells, particularly in neuronal cells, by administering asuitable inhibitor of phospholipase A₂ activity, typically an inhibitorof cPLA₂.

WO 97/21676 Patent discloses certain azetidinone compounds asphospholipase inhibitors in the treatment of atherosclerosis.

U.S. Pat. No. 5,453,443 discloses a series of biaryl ketones which arereported to inhibit PLA₂ enzymes. These compounds have the genericformula

wherein:

-   -   R¹ is selected from        -   (a) hydrogen,        -   (b) —C₁₋₆ alkyl, and        -   (c) —C₁₋₆ alkyl-phenyl;    -   or wherein R¹ and R⁵ are joined such that together with the        carbon atoms to which they are attached there is formed a        saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8        atoms;    -   R² and R³ are each independently selected from        -   (a) hydrogen,        -   (b) —C₁₋₆ alkyl, and        -   (c) —C₁₋₆ alkyl-phenyl;    -   or wherein two R² or two R³ are joined such that together with        the carbon atoms to which they are attached there is formed a        saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8        atoms;    -   R⁵ is as defined above or is selected from        -   (a) hydrogen        -   (b) —C₁₋₆ alkyl,        -   (c) —C₁₋₆ alkyl-phenyl C₁₋₆ alkyl,        -   (d) —OH,        -   (e) —O—C₁₋₆ alkyl, or        -   (f) —C₁₋₆ alkyl-phenyl C₁₋₆ alkyl;    -   R⁶ is selected from        -   (a) hydrogen        -   (b) —C₁₋₆ alkyl, and        -   (c) —C₁₋₆ alkyl-phenyl, wherein the phenyl is optionally            substituted with C₁₋₂ alkyl;        -   (d) —OH,        -   (e) —O—C₁₋₆ alkyl, or        -   (f) —O—C₁₋₆ alkyl-phenyl, wherein the phenyl is optionally            substituted with C₁₋₂ alkyl;    -   or wherein two R⁶ are joined to form O═ or are joined together        such that together with the carbon atom to which they are        attached there is formed a saturated or unsaturated carbon ring        of 3, 4, 5, 6, 7 or 8 atoms;    -   R⁸, R⁹ and R¹⁴ are each independently selected from        -   (a) H,        -   (b) —C₁₋₆ alkyl,        -   (c) halo        -   (d) —CN,        -   (e) —OH,        -   (f) —OC₁₋₆ alkyl,        -   (g) —OC₁₋₆ alkyl-phenyl,        -   (h) —SR¹¹,        -   (i) S(O)R¹¹, or        -   (j) S(O)₂R¹¹;    -   R¹⁰, R¹⁵, R¹⁶ and R¹⁷ are each independently selected from        -   (a) hydrogen,        -   (b) —C₁₋₆ alkyl, and        -   (c) —C₁₋₆ alkyl-phenyl;    -   R¹¹ is selected from        -   (a) —C₁₋₆ alkyl,        -   (b) —C₂₋₆ alkenyl,        -   (c) —CF₃,        -   (d) -phenyl(R¹²)₂, or        -   (e) —C₂₋₆ alkenyl-phenyl(R¹²)₂,    -   R¹² is        -   (a) hydrogen,        -   (b) —C₁₋₆ alkyl,        -   (c) Cl, F, I or Br;    -   R¹³ is perfluoroC₁₋₆alkyl;    -   A and B are each independently        -   (a) covalent bond,        -   (b) O,        -   (c) S,        -   (d) S(O), or        -   (e) S(O)₂;    -   Q is selected from        -   (a) —CH(OH)R¹³,        -   (b) —COR¹³,        -   (c) —COR¹⁶, or        -   (d) —C₁₋₆ alkylCOCOOR¹⁷;    -   X¹ is selected from        -   (a) —O—,        -   (b) —S—,        -   (c) —S(O)—,        -   (d)    -   Z is        -   (a) H, or        -   (b) -phenyl-(R¹⁴)₃,    -   m is 0, 1, 2, 3 or 4;    -   n is 2, 3, 4, 5, 6 or 7; and    -   r and s are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

Published application WO 99/15129 discloses selective cPLA₂ inhibitorshaving the formula

-   -   wherein W is CH═CH, CH═N, O or S;    -   R¹ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, halo, hydroxy, cyano,    -    in which R² and R³ are each independently hydrogen or        (C₁-C₆)alkyl, —COO—(C₁-C₆)alkyl, CF₃, (C₁-C₆)alkylphenyl, phenyl        or phenyl substituted by one or more, preferably 1-3, of        (C₁-C₆)alkyl, —COO—(C₁-C₆)alkyl,    -    in which R² and R³ are as defined above, halo, hydroxy,        —O—(C₁-C₆)alkyl, —S—(C₁-C₆)alkyl or (C₂-C₆)alkenyl;    -   p is 0, 1 or 2;    -   A is V—(R^(c))_(n)—;    -   R^(c) is a straight or branched chain alkyl group;    -   n is 0 or an integer of from 1 to 6;    -   R^(a) and R^(b) when taken together form an oxo (═O) group, or        R^(a) and R^(b) are each independently hydrogen or OH;    -   V is O, —S—, —SO—, —SO₂, —CONH or NHCO when n is an integer of        from 1 to 6 or V is (C₂-C₆) alkenyl or a bond when n is 0 or an        integer of from 1 to 6;    -   D is —(CH₂)_(m) or a bond linking the    -    ring to Y;    -   m is an integer of from 1 to 6;    -   Y is —O—, —S—, —SO—, —SO₂;    -    or a bond;    -   R⁴ is as defined below for R⁷;    -   Z is    -   in which B is:    -   X is S or O;    -   q is an integer from 1 to 6;    -   R⁹ is hydrogen or (C₁-C₆)alkyl;    -   R¹⁰ is hydrogen, CN, NO₂, OH, —O—(C₁-C₆)alkyl, (C₁-C₆) alkyl,        phenyl or (C₁-C₆)alkylphenyl;    -   R⁵ and R⁶ are each independently hydrogen or (C₁-C₁₈) alkyl;    -   R⁷ and R⁸ are each independently        -   (a) hydrogen;        -   (b) (C₁-C₁₈)alkyl;        -   (c) (C₁-C₁₈)alkyl substituted by one or more of            -   (1) phenyl;            -   (2) phenyl substituted by 1-5 fluoro, 1-3 (for each of                the following phenyl substituents) halo (other than                fluoro), 1-3 (C₁-C₆)alkoxy, 1-3(C₁-C₆)alkyl, nitro,                cyano, hydroxy, trifluoromethyl, (C₁-C₆)alkylthio,                amino, 1-3 (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino,                —CO₂H, —COO—(C₁-C₆)alkyl, —SO₃H, —SO₂NHR¹⁵ in which R¹⁵                is hydrogen or (C₁-₆)alkyl, or            -    in which R² and R³ are as defined above;            -   (3) heterocyclic selected from oxadiazolyl, isoxazolyl,                oxazolyl, furyl and thiazolyl;            -   (4) heterocyclic substituted by one or more of,                preferably 1-3, phenyl, phenyl substituted by 1-3 (for                each of the following) halo, (C₁-C₆)alkoxy,                (C₁-C₆)alkyl, nitro, cyano, hydroxy, trifluoromethyl,                (C₁-₆)alkylthio, amino, (C₁-C₆)alkylamino,                di(C₁-C₆)alkylamino, CO₂H, —OO—(C₁-C₆)alkyl, —SO₃H,                SO₂NHR¹⁵ in which R¹⁵ is hydrogen or (C₁-C₆)alkyl, or            -    in which R² and R³ are as defined above, (C₁-C₆)alkyl                or (C₁-C₆)alkyl substituted by one or more, preferably                1-3, phenyl or heterocyclic groups, said phenyl or                heterocyclic group being unsubstituted or substituted by                1-3 (for each of the following) halo, 1-3 (C₁-C₆)alkoxy,                1-3 (C₁-C₆)alkyl, nitro, cyano, hydroxy,                trifluoromethyl, (C₁-C₆)alkylthio, amino, 1-3                (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, COOH,                —COO—(C₁-C₆)alkyl, —SO₃H, —SO₂NHR¹⁵ in which R¹⁵ is                hydrogen or (C₁-C₆)alkyl, or            -    in which R² and R³ are each independently hydrogen or                (C₁-C₆)alkyl, the heterocyclic radical being selected                from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl,                pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;            -   (5) carboxy or —COO—(C₁-C₆)alkyl;            -   (6) hydroxy, halo, —O—(C₁-C₆) alkyl or —S—(C₁-C₆)alkyl,                with the proviso that the OH, ethers or thioethers                cannot be on the carbon bearing the heteroatoms;            -   (7) cyano;            -   (8) halo, trifluoromethyl or trifluoroacetyl;            -   (9) CH₂ L—R¹⁶ in which L is            -    or —O—SiR¹⁶R¹⁸R¹⁹ or a bond in which R¹⁶ and R¹⁷ are                each independently (C₁-C₁₈)alkyl or (C₂-C₁₈)alkenyl or                (C₁-C₁₈)alkyl or (C₂-C₁₈)alkenyl substituted by one or                more, preferably 1-3, phenyl or heterocyclic radicals,                said phenyl or heterocyclic radicals being unsubstituted                or substituted by 1-5 fluoro, 1-3 halo (other than                fluoro), 1-3 (C₁-C₆)alkoxy, 1-3(C₁-C₆)alkyl, nitro,                cyano, hydroxy, 1-3 trifluoromethyl, 1-3                (C₁-C₆)alkylthio, amino, 1-3(C₁-C₆)alkylamino, 1-3                di(C₁-C₆)alkylamino, CO₂H, 1-3 —COO(C₁-C₆)alkyl,            -    or —SO₂NHR⁹ in which R⁹ is hydrogen or (C₁-C₆)alkyl and                R² and R³ are as defined above;    -   in which B¹ is    -    —SO₂—, —PO(OR⁹)₂ or a bond; providing that when B¹ is        —PO(OR⁹)₂, then R⁷ becomes R⁹, and when B¹ is    -    or —SO₂—, then R⁷ cannot be hydrogen;    -   X, q, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined in (a);    -   in which q, R⁵ and R⁶ are as defined above;    -   R¹⁸, R¹⁹ and R¹¹ are as defined above for R⁷ and R⁸ except that        they may not be hydrogen, or R¹⁸ and R¹⁹ taken together with the        nitrogen to which they are attached represent a 4, 5- or        6-membered heterocyclic ring and Y, R⁷ and R¹¹ are as defined        above, or R¹⁸, R¹⁹ and R¹¹ taken together with the nitrogen to        which they are attached represent pyridinium, said pyridinium        group being unsubstituted or substituted by (C₁-C₁₂)alkyl,        (C₁-C₁₂)alkoxy, amino, (C₁-C₁₂)alkylamino, di(C₁-C₁₂)alkylamino,    -    in which R² and R³ are as defined above, phenyl or phenyl        (C₁-C₁₀)alkyl;    -   in which R¹³ is (C₁-C₁₈)alkyl or (C₁-C₁₈)alkyl substituted by        carboxy,    -    in which R² and R³ are as defined above, hydroxy, —O—(C₁-C₆)        alkyl, —O—(C₁-C₆) alkyl or —S—(C₁-C₆) alkyl substituted by 1 or        2 phenyl or substituted phenyl groups, the substituents for the        substituted phenyl groups being 1-5 fluoro or 1-3 (for each of        the following phenyl substituents) halo (other than fluoro),        (C₁-C₆)alkoxy, (C₁-C₆)alkyl, nitro, cyano, hydroxy,        trifluoromethyl, (C₁-C₆)alkylthio, amino, (C₁-C₆) alkylamino,        di(C₁-C₆) alkylamino, CO₂H, COO—(C₁-C₆) alkyl, SO₃H, SO₂NHR¹⁵ in        which R¹⁵ is hydrogen or (C₁-C₆) alkyl or    -    in which R² and R³ are as defined above;    -   r is 0 or an integer of from 1 to 3;    -   R⁷ is as defined above;    -   M is —(CH₂—)_(m)T where T is    -    in which R² is as defined above, —SO₂— or a bond when MR⁷ is on        nitrogen and providing that when T is    -    or —SO— or —SO₂—, then R⁷ cannot be hydrogen, and T is    -    or a bond when MR⁷ is on a carbon atom of the heterocyclic        ring;    -   R¹⁴ is hydrogen or (C₁-C₆)alkyl;    -   m is 0 or an integer of 1-6;    -   wherein Q is —O—, —S—, —SO— or —SO₂—, and q, R⁵, R⁶ and R⁷ are        as defined above, providing that when Q is —SO— or —SO₂—, R⁷        cannot be hydrogen;        -   (f) R⁷ wherein R⁷ is defined above, providing that when Y is            —SO— or —SO₂—, R⁷ cannot be hydrogen; and    -   R¹⁸ and R¹⁹ are phenyl or phenyl substituted by 1-3 halo,        (C₁-C₆)alkoxy, (C₁-C₆)alkyl, nitro, cyano, hydroxy,        trifluoromethyl, (C₁-C₆)alkylthio, amino, (C₁-C₆)alkylamino,        di(C₁-C₆)alkylamino, CO₂H, —COO—(C₁-C₆)alkyl, —SO₃H, SO₂NHR¹⁵ in        which R¹⁵ is hydrogen or (C₁-C₆)alkyl, or    -    in which R² and R³ are as defined above; or pharmaceutically        acceptable salts, solvates or prodrugs thereof.    -   R¹⁸ and R¹⁹ are phenyl or phenyl substituted by 1-3 halo,        (C₁-C₆)alkoxy, (C₁-C₆) alkyl, nitro, cyano, hydroxy,        trifluoromethyl, (C₁-C₆) alkylthio, amino, (C₁-C₆) alkylamino,        di(C₁-C₆)alkylamino, CO₂H, —COO—(C₁-C₆)alkyl, —SO₃H, SO₂NHR¹⁵ in        which R¹⁵ is hydrogen or (C₁-C₆)alkyl, or    -    in which R² and R³ are as defined above; or pharmaceutically        acceptable salts, solvates or prodrugs thereof.

There is nothing in any of the foregoing references, or in the generalprior art, to suggest the novel alpha-amino, thio, oxo substitutedketones of the present invention as cytosolic phospolipase A2inhibitors.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel alpha- andgamma-hetero substituted ketone compounds which inhibit cytosolicphopholipase A2 enzymes that are pro-inflammatory mediators.

This invention relates to novel cytosolic phospholipase inhibitorsrepresented by formula I, or a pharmaceutically acceptable salt thereof

-   -   wherein X₁ is O, S(O)_(n),    -    or —CH₂—, with the proviso that when X₁ is —CH₂—, R₁ and R₂ are        only halogen;    -   n is 0, 1 or 2;    -   R^(a) and R^(b) when taken together form an oxo (═O) group, or        R^(a) and R^(b) are each independently hydrogen, OH, OCOR⁹, NH₂,        N₃, NHCOOR⁹, NHCOCOR⁹, NHSO₂R⁹ or F;    -   X is H, CF₃, OCF₃, halogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇        alkynyl or C₃-C₇ cycloalkyl, said alkyl, alkenyl, alkynyl or        cycloalkyl group being optionally substituted by COOR⁸, CN,        C(O)NR⁶R⁷, PO₃R⁸, SO₃R⁸, heterocyclic, OR⁸, SH, S(O)_(n)R⁹,        NR⁶R⁷, NH(CO)NR⁶R⁷, NH(CO)OR⁹, aryl or heteroaryl, said aryl or        heteroaryl being optionally substituted by one or two groups        independently selected from NR⁶R⁷, OR⁸, COOR⁸, SO₃R⁸, OCOR⁹,        PO₃R⁸, C(O)NR⁶R⁷ or heterocyclic;    -   R¹ and R² are each independently H, halogen, OR⁹, C₁-C₇ alkyl,        C₂-C₇ alkynyl, C₂-C₇ alkenyl or C₃-C₇ cycloalkyl, said alkyl,        alkenyl, alkynyl or cycloalkyl group being optionally        substituted by COOR⁸, CN, C(O)NR⁶R⁷, PO₃R⁸, SO₃R⁸, heterocyclic,        OR⁸, SH, S(O)_(n)R⁹, NR⁶R⁷, NH(CO)NR⁶R⁷, NH(CO)OR⁹, OC(O)OR⁹,        aryl or heteroaryl, said aryl or heteroaryl being optionally        substituted with one or two groups independently selected from        NR⁶R⁷, OR⁸, COOR⁸, SO₃R⁸, OCOR⁹, PO₃R⁸, C(O)NR⁶R⁷ or        heterocyclic;    -   R³, R⁴ and Y are each independently H, halogen, OR¹⁰,        S(O)_(n)R¹⁰, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₇        cycloalkyl, said alkyl, alkenyl, alkynyl or cycloalkyl group        being optionally substituted by COOR⁸, CN, C(O)NR⁶R⁷, PO₃R⁸,        SO₃R⁸, heterocyclic, OR⁸, SH, S(O)_(n)R⁹, NR⁶R⁷, NH(CO)NR⁶R⁷,        NH(CO)OR⁹, OC(O)OR⁹, aryl or heteroaryl, said aryl or heteroaryl        being optionally substituted by one or two groups independently        selected from NR⁶R⁷, OR⁸, COOR⁸, SO₃R⁸, OCOR⁸, PO₃R⁸, C(O)NR⁶R⁷        or heterocyclic, with the proviso that not all of R³, R⁴ and Y        may be the same halogen;    -   R⁵, R⁶ and R⁷ are each independently H, C₁-C₇ alkyl, C₂-C₇        alkenyl, C₂-C₇ alkynyl or C₃-C₇ cycloalkyl, said alkyl, alkenyl,        alkynyl or cycloalkyl group being optionally substituted by        COOR⁸, CN, OR⁸, NR⁸R⁹, SO₃R⁸, PO₃R⁸, halogen, aryl or        heteroaryl, said aryl or heteroaryl being optionally substituted        by one or two groups independently selected from COOR⁸, SO₃R⁸,        PO₃R⁸ or heterocyclic;    -   R⁸ is H, C₁-C₇ saturated straight chain alkyl or cycloalkyl, CF₃        or CH₂CF₃;    -   R⁹ is same as R⁸ but is not hydrogen;    -   R¹⁰ is C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₇        cycloalkyl, said alkyl, alkenyl, alkynyl or cycloalkyl group        being optionally substituted by COOR⁸, CN, C(O)NR⁶R⁷, PO₃R⁸,        SO₃R⁸, heterocyclic, OR⁸, SH, S(O)_(n)R⁹, NR⁶R⁷, NH(CO)NR⁶R⁷,        NH(CO)OR⁹, aryl or heteroaryl, said aryl or heteroaryl being        optionally substituted by one or two groups independently        selected from NR⁶R⁷, OR⁸, COOR⁸, SO₃R⁸, OCOR⁸, PO₃R⁸, C(O)NR⁶R⁷        or heterocyclic;    -   Z is OR¹¹, S(O)_(n)R¹¹, NR¹¹R¹² or CHR¹¹R¹²;    -   R¹¹ and R¹² are each independently hydrogen, C₁-C₇ alkyl, C₂-C₇        alkenyl, C₂-C₇ alkynyl or C₃-C₇ cycloalkyl, said alkyl, alkenyl,        alkynyl or cycloalkyl group being optionally substituted by        NR¹³R¹⁴, S(O)_(n)R¹³ or OR¹³, with the proviso that both R¹¹ and        R¹² may not be hydrogen;    -   R¹³ and R¹⁴ are each independently H, SiR¹⁵R¹⁶R¹⁷, C₁-C₇ alkyl,        C₂-C₇ alkenyl, C₂-C₇ alkynyl, aryl or C₃-C₇ cycloalkyl, said        alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being        optionally substituted by one to three groups independently        selected from COOR⁸, OR⁸, SiR¹⁵R¹⁶R¹⁷, OR¹⁵, aryl, biaryl or        heteroaryl, said aryl, biaryl or heteroaryl being optionally        substituted with one to three groups independently selected from        halogen, CF₃, OR⁸, COOR⁸, NO₂, or CN;    -   R¹³ and R¹⁴ when taken together may form a 5-7 membered        heterocyclic ring with one or more heteroatoms selected from O,        N and S; said ring being optionally substituted by OR⁸, COOR⁸,        or C(O)NR⁵R⁶;    -   R¹⁵, R¹⁶, R¹⁷ are each independently aryl, benzyl, benzhydryl,        biaryl, heteroaryl, (C₁-C₆) alkyl-aryl or (C₁-C₆)        alkyl-heteroaryl, said aryl radical being optionally substituted        by halogen, CF₃, OR⁸, COOR⁸, NO₂, CN, or C₁-C₇ alkyl.

This invention also provides methods for inhibiting cytosolic PLA₂ in amammal in need thereof which comprise administering to said mammal atherapeutically effective amount of a compound of formula I and methodsfor using the compounds of formula I to treat various diseasescharacterized by inappropriate activation of the cytosolic PLA₂ enzymessuch as asthma, allergic rhinitis, cerebral ischemia, Alzheimer'sDisease, rheumatoid arthritis, acute pancreatitis, inflammatory boweldisease, psoriasis, gout, neutrophil and platelet activation, chronicskin inflammation, shock, trauma-induced inflammation such as spinalcord injury, damage to the skin resulting from UV light or burns andmacrophage activation. In further aspects, the present inventionprovides pharmaceutical compositions comprising a therapeuticallyeffective amount of a compound of formula I and a pharmaceuticallyacceptable carrier and processes for preparing the compounds of formulaI.

DETAILED DESCRIPTION

The object of this invention was to discover a selective cPLA₂ inhibitorwhich is active, both topically and orally, in treating inflammatorydisease of the skin and other tissues as well as other chronic and acuteconditions which have been linked to inappropriate activation of thecPLA₂ enzymes. Preferably such compound would also be devoid ofundesirable lipid-perturbing activities associated with skin irritation.

The above-mentioned objectives have been met by the compounds of formulaI described above.

Definitions

In the present application the numbers in the subscript after the symbol“C” define the number of carbon atoms a particular group can contain.For example, “C₁-C₇ alkyl” refers to straight and branched chain alkylgroups with 1 to 7 carbon atoms. Similarly, “C₂-C₇ alkenyl” or “alkynyl”refers to an unsaturated hydrocarbon group containing form 2 to 7 carbonatoms and at least one carbon-carbon double bond or triple bond.

The term “halogen” or “halo” as used herein refers to fluorine,chlorine, bromine or iodine, preferably fluorine and chlorine.

“Aryl” as used herein refers to a C₆ monocyclic aromatic ring system ora C₉ or C₁₀ bicyclic carbocyclic ring system having one or two aromaticrings such as phenyl or naphthyl. It may also refers to a C₁₄ tricycliccarbocyclic ring system having two or three aromatic rings such asanthracenyl or phenanthrenyl. Unless otherwise indicated, “substitutedaryl” refers to aryl groups substituted with one or more (preferablyfrom 1 to 3) substituents independently selected from (C₁-C₆)alkyl,haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-carbonyl, (C₁-C₆)alkanoyl,hydroxy, halo, mercapto, nitro, amino, cyano, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, carboxy, aryl, aryl (C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy, heterocyclic, heterocyclic (C₁-C₆)alkyl and the like. Theterm “biaryl” refers to two C₆ monocyclic aromatic ring systems or twoC₉ or C₁₀ bicyclic carbocyclic ring systems linked together such as o-,m- and p-biphenyl or o-, m- and p-binaphthyl. The term “heteroaryl”refers to a 5- or 6-membered aromatic ring system or a 9- or 10-memberedbicyclic aromatic ring system containing one, two or three heteroatomsselected from N, O and S. The term “benzhydryl” refers to a carbon atombearing two aryl, bis-aryl or heteroaryl groups.

The term “heterocyclic” as used herein refers to a 4-, 5- or 6-memberedring containing one, two or three heteroatoms selected from N, O and S.The 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3double bonds. The nitrogen heteroatoms can be optionally quaternized orN-oxidized. The sulfur heteroatoms can be optionally S-oxidized. Theterm “heterocyclic” also includes bicyclic groups in which any of theabove heterocyclic rings is fused to a benzene ring or a cyclohexanering or another heterocyclic ring. Heterocyclics include: pyrrolyl,pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,imidazolyl, imidazolidinyl, pyridyl, piperidyl, pyrazinyl, piperazinyl,pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl,isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl,benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furyl,dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, dioxolanyl,thienyl, benzothienyl and diaxanyl.

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to include such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms, andpharmaceutically acceptable salts thereof.

As mentioned above the invention also includes pharmaceuticallyacceptable salts of the compounds of formula I. A compound of theinvention can possess a sufficiently acidic, a sufficiently basic, orboth functional groups. Accordingly, a compound may react with any of anumber of inorganic bases, and organic and inorganic acids, to form apharmaceutically acceptable salt.

The term “pharmaceutically acceptable salt” as used herein refers tosalts of the compounds of formula I which are substantially non-toxic toliving organisms. Typical pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid oran inorganic base. Such salts are known as acid addition and baseaddition salts.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate,dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propionate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylene-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,napthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. Suitable organic bases include trialkylaminessuch as triethylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N′-dibenzylethylene-diamine,dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine,or the like pharmaceutically acceptable amines. The potassium and sodiumsalt forms are particularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole.

A preferred embodiment of the present invention includes compounds andpharmaceutically acceptable salts thereof in which R³, R⁴ and Y are eachindependently H, halogen, OR¹⁰, S(O)_(n)R¹⁰, C₁-C₇ alkyl, C₂-C₇ alkenyl,C₂-C₇ alkynyl or C₃-C₇ cycloalkyl, said alkyl, alkenyl, alkynyl orcycloalkyl group being optionally substituted by COOR⁸, CN, C(O)NR⁶R⁷,PO₃R⁸, SO₃R⁸, heterocyclic, OR⁸, SH, S(O)_(n)R⁹, NR⁶R⁷, NH(CO)NR⁶R⁷,NH(CO)OR⁹, OC(O)OR⁹, aryl or heteroaryl, said aryl or heteroaryl beingoptionally substituted by one or two groups independently selected fromNR⁶R⁷, OR⁸, COOR⁸, SO₃R⁸, OCOR⁸, PO₃R⁸, C(O)NR⁶R⁷ or heterocyclic, withthe proviso that not all of R³, R⁴ and Y may be the same halogen.

Within this embodiment, more preferred compounds are those in which X₁is O, S(O)_(n) or —CH₂— with the proviso that when X₁ is —CH₂—, R₁ andR₂ are only halogen and Y is OR¹⁰ or S(O)_(n)R¹⁰ in which R¹⁰ is C₁-C₇alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₇ cycloalkyl, said alkyl,alkenyl, alkynyl or cycloalkyl group being optionally substituted byCOOR⁸, CN, C(O)NR⁶R⁷, PO₃R⁸, SO₃R⁸, heterocyclic, OR⁸, SH, S(O)_(n)R⁹,NR⁶R⁷, NH(CO)NR⁶R⁷, NH(CO)OR⁹, OC(O)OR⁹, aryl or heteroaryl, said arylor heteroaryl being optionally substituted by one or two groupsindependently selected from NR⁶R⁷, OR⁸, COOR⁸, SO₃R⁸, OCOR⁸, PO₃R⁸,C(O)NR⁶R⁷ or heterocyclic. The above embodiment in which R^(a) and R^(b)are each independently hydrogen or OH is a most preferred embodiment.Another most preferred embodiment comprises compounds in which R^(a) andR^(b) are each independently hydrogen, F, OCOR⁹, NH₂, N₃, NHCOOR⁹ orNHCOCOR⁹ in which R⁹ is as defined above.

For all of the above-described embodiments, the most preferred Zsubstituent is

in which m and p each independently represent an integer of one to six,R¹⁵, R¹⁶, R¹⁷ are each independently C₁-C₇ alkyl, R¹⁸ is C₁-C₇ alkyl andaryl represents

in which X¹ is halogen.

The present invention also includes solvated forms of the compounds offormula I, particularly hydrates, in which the ketone group exists as amixture of ketonic I and hydrated forms II and are each independentlyinterconvertible and pharmacologically active.

Biological Activity

Assay for determining activity as cPLA₂ inhibitors:

³H-arachidonate-labeled U937 membranes were prepared from U937 cellsgrown in RPMI 1640 medium containing L-glutamine supplemented with 10%fetal calf serum and 50 μg/ml gentamycin in a 5% CO₂ incubator at 37° C.Sixteen hours prior to harvesting the cells, ³H-arachidonate (100Ci/mmol) was added to the cell culture (1×10⁶ cells/ml, 0.5 μCi/ml).After washing the cells with HBSS (Hank's Balanced Salts) containing 1mg/ml HSA (Human Serum Albumin), the cells were lysed by nitrogencavitation and the homogenate was centrifuged at 2,000×g for 10 minutes.The supernatant was further centrifuged at 50,000×g for 30 minutes afterwhich the pellet was resuspended in water and autoclaved at 120° C. for15 minutes to inactivate any residual phospholipase A₂ activity. Thissuspension was then recentrifuged at 50,000×g for 30 minutes and thepellet resuspended in distilled water.

Assays of cPLA₂ activity using these ³H-arachidonate-labeled U937membranes as substrate typically employ human recombinant cPLA₂ (seeBurke et al., Biochemistry 34: 15165-15174, 1995) and membrane substrate(22 μm phospholipid) in 20 mm HEPES[N-(2-hydroxyethyl)piperazine-N¹-(2-ethanesulfonic acid)] buffer, pH 8,containing 6 mm CaCl₂, 0.9 mg/ml albumin and 4 m glycerol. Enzyme assaysare allowed to proceed for 3 hours at 37° C. before removing thenon-hydrolyzed membranes. The hydrolyzed, radiolabeled fatty acid isthen measured by liquid scintillation counting of the aqueous phase.

The effects of inhibitor are calculated as percent inhibition of³H-arachidonate formation, after correcting for nonenzymatic hydrolysis,as compared to a control lacking inhibitor according to the followingformula:percent inhibition=((Control DPM−Inhibitor DPM)/Control DPM)×100%

Various concentrations of an inhibitor were tested, and the percentinhibition at each concentration was plotted as log concentration(abscissa) versus percent inhibition (ordinate) to determine the IC₅₀values.

In this assay the compounds of Examples 1-39 below exhibited cPLA₂ IC₅₀values in the range of from about 1 to 50 μm.

Since the compounds of the present invention are selective inhibitors ofcytosolic phospholipase A₂, they are of value in the treatment of a widevariety of clinical conditions.

Inflammatory disorders which may be treated by inhibition of cytosoliccPLA₂ include such conditions as arthritis, psoriasis, asthma,inflammatory bowel disease, gout, trauma-induced inflammation such asspinal cord injury, Alzheimer's Disease, cerebral ischemia, chronic skininflammation, shock, damage to skin resulting from exposure toultraviolet light or burns, allergic rhinitis, acute pancreatitis, andthe like.

The compounds of the present invention have also been found to be verystable towards keto-reduction. It has been shown that a reliable methodto assess keto-stability of compounds is to measure the percent of suchcompounds remaining after incubation with erythrocyte lysates[Rady-Pentek P., et al., Eur. J. Clin. Pharmacol., 1997, 52(2):147-153]. The assay is the following.

Male Wistar rates were anesthetized with CO₂ and then blood was removedby direct cardio-puncture or through a pre-inserted jugular vein canulainto syringes that were pre-rinsed with heparin. The blood was theninserted into heparanized tubes and placed on ice. The blood wascentrifuged at 3000 rpm for 5 minutes to separate the plasma. The plasmawas removed and an equivalent volume of sterile water was mixed with theerythrocyte fraction. This was mixed by inversion and left on ice forseveral minutes to lyse the erythrocytes. The erythrocyte-water mixturewas then centrifuged at 3000 rpm for 5 minutes to pellet the cellulardebris.

Each compound was dissolved in methanol (1 ml) to produce a 2 mMsolution. From this solution, 50 μl aliquot was made up to 1 ml in 50%methanol to produce a 100 μM stock solution. From this solution, a dosesolution was prepared by diluting 100 μl to 2 ml of a 0.1 M potassiumphosphate buffer (pH=7.4) to produce a 2 μM final incubation dilution.

The lysate (250 μl) was then aliquoted into eppendorf tubes, 6 for eachcompound, i.e. 0 time, 15 minutes, 60 minutes in duplicate. To thesealiquots was added 200 μl of the dose solution and this was preheated to37° C. for 2-3 minutes prior to the addition of NADPH (1 mM finalconcentration) to start the reactions. The reactions were terminatedwith the addition of either 0.5 ml or 1 ml of acetonitrile. Followingcentrifugation at 8000×g for 5 minutes, the supernatant was removed andstored at −20° C. until analysis could proceed by quantitative LC/MS.Samples were analyzed by electrospray ionization (ESI) on a MicromassZMD 2000® single quadrupole mass spectrometer coupled to a Shimadzu HPLCsystem. The percent of compound remaining following 15 minutes and 60minutes incubation is calculated relative to the 0 time point.

Administration Modes

The compounds of formula I are usually administered in the form ofpharmaceutical compositions. They can be administered by a variety ofroutes including oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, and intranasal. The compounds are effective as bothinjectable and oral compositions. Such compositions are prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound defined by formula I and a pharmaceutically acceptablecarrier.

In making the compositions employed in the present invention the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within a carrier which can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semisolid, or liquid material, which acts asa vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quicksustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 5 to about 100 mg, more usually about 10 toabout 30 mg, of the active ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The active compound is effective over a wide dosage range. For example,dosages per day normally fall within the range of about 0.5 to about 30mg/kg of body weight. In the treatment of adult humans, the range ofabout 1 to about 15 mg/kg/day, in single or divided dose, is especiallypreferred. However, it will be understood that the amount of thecompound actually administered will be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered, the age, weight, and response of the individual patient,and the severity of the patient's symptoms, and therefore the abovedosage ranges are not intended to limit the scope of the invention inany way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day.

The compounds of the present invention can be prepared by variousmethods which are known in the art. Illustrative methods of preparationare provided in the reaction schemes which follow and in the Examples.

Method of Preparation

Preparation of compounds of formula I may be accomplished via one ormore of the synthetic schemes which are described below.

Scheme A describes a method of preparing compounds of generic structure6. Reaction of phenol 1 in which P is a protecting group such astert-butyl diphenylsilyl with a bromo ester such as methyl bromoacetatein a solvent like acetonitrile or N,N-dimethylformamide in presence of abase such as potassium carbonate affords 2. Deprotection of 2 with areagent such as tetrabutyl ammonium fluoride gave the alcohol 2 (P═H)that was activated via a group like a mesyloxy to give 3 (L═Ms).Reaction of 3 with a secondary amine R¹R²NH in a solvent such asacetonitrile gave the amine 4. Reaction of 4 with atrimethylsilylfluoroalkyl reagent such as trifluoromethyltrimethylsilanein a solvent such as toluene using a catalyst like tetrabutylammoniumfluoride gave, after aqueous hydrolysis, ketone 6. Alternatively, theester 4 can be saponified to the acid 5 by a base such as potassiumhydroxide and in a solvent such as aqueous ethanol. The acid 5 can bereacted with a reagent such as oxalyl chloride to give an intermediateacid chloride which is then treated with an anhydride such astrifluoroacetyl anhydride or chlorodifluoroacetic anhydride and a basesuch as pyridine in a solvent like toluene to give the ketone 6.

Scheme B describes the preparation of compounds of general structure 11.Reaction of phenol 1 in which P is a protecting group such astert-butyldiphenylsilyl with an epoxide such as 7 in a solvent such asN,N-dimethylformamide catalysed by a base such as1,4-diazabicyclo[2,2,2]octane afforded 8. Alternatively, reaction of aphenol 7b with an epoxide 1b in which R^(a) and R^(b) can be an hydrogenatom or a lower alkyl like methyl also gave compound 8. Compound 8 canbe oxidized to the ketone 9 by reaction with an oxidant such as1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) in a solvent like dichloromethane. Deprotection of thesilyl group P in 9 with a reagent such as tetrabutylammonium fluorideand in a solvent like tetrahydrofuran gave the alcohol 9 (P═H). Reactionof the alcohol 9 (P═H) with an alkyl or arylsulfonyl chloride such asmethanesulfonyl chloride gave a sulfonate ester 9 (P═Ms) that wasreacted with a secondary amine of general formula R²R³NH in a solventlike acetonitrile to give 10. Reaction of 10 (R¹═tBu) with an acid suchas trifluoroacetic acid or hydrochloric acid in a solvent likedichloromethane yielded the amine 11 as the corresponding salt.

Scheme C describes the preparation of compounds of esters or amides ofgeneral structure 13 or 16. Reaction of alcohol 12 with an acidanhydride or an acid chloride in presence of a base such as pyridinegave an ester of general structure 13. Alcohol 12 can also be reactedunder Mitsunobu condition with hydrazoic acid or an equivalent azidesource to give the azido derivative 14. The azido derivative 14 can bereduced to the amine derivative 15 with a reducing agent liketriphenylphosphine and water. Reaction of the amine derivative 15 withan acyl chloride such as acetyl chloride or pyruvyl chloride gave theamide 16 after deprotection of the benzoic ester. Alternatively 16 canbe obtained by coupling of an acid R⁵CO₂H with the amine 15 in presenceof a coupling reagent such as dicyclohexylcarbodiimide or2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) followed bydeprotection.

Scheme D describes the preparation of compounds wherein R¹ is OR⁹.Hence, the various alkyl dialkoxyacetates 17 may be treated with achlorinating agent such as phosphorous pentachloride to give thecorresponding chlorides 18. Substitution of these chlorides with phenol1 afford compound of type 19. Deprotection of 19 with a reagent such astetrabutylammonium fluoride gave the alcohol (P═H) that was activatedvia a group like a mesyloxy. Reaction of this compound with a secondaryamine R¹R²NH in a solvent such as acetonitrile gave the amine 20.Saponification of the ester in conditions known in the art followed byactivation with oxalyl chloride gave the corresponding acid chloridewhich was then converted to the Weinreb amide 21 in the usual acylationconditions. Reaction of this compound with a lithium derivative of type24 afford the coupling adduct 22 which was then hydrolyzed to the acid23.

Scheme E shows a method of preparing compounds of general structure 34.Reaction of 4-methoxybenzaldehyde 25 and a bromodifluoro ester such asethyl bromodifluoroacetate with zinc in a solvent like tetrahydrofuranunder Reformatsky conditions gave the alcohol 26. Reaction of thealcohol 26 with an alkyl or aryl sulfonyl chloride such asmethanesulfonyl chloride in a solvent like dichloromethane gave anintermediate sulfonate ester. This intermediate sulfonate was treatedwith sodium iodide in a solvent like acetone to give the iodide 27.Alternatively, the alcohol 26 can be reacted with an arylchlorothionoformate such as phenylchlorothionoformate to give thephenylthianocarbonate 28. The iodide 27 or the phenylthianocarbonate 28were then reacted with an alkyltin hydride such as tributyltin hydridein presence of 2,2′-azobisisobutyronitrile and in a solvent such asbenzene to give the de-oxygenated ester 29. Compound 29 was then treatedwith a reagent such as boron tribromide to give the phenol 30. Reactionof the phenol 30 with an alcohol of general formula R²OH under Mitsunobuconditions gave the ether 31. Alternatively, the phenol 30 can bealkylated with a substituted alkyl halide (R²X) using a basic catalystsuch as potassium carbonate and in a solvent such as acetonitrile ordimethylformamide to give the ether 31. Compound 31 was then saponifiedto the acid 32 by treatment with a base such as sodium hydroxide orpotassium hydroxide in a solvent such as aqueous ethanol followed byacidification with a diluted acid. The acid 32 was then activated as themixed anhydride by reaction with an alkyl chloroformate such as isobutylchloroformate in presence of a base such as N-methylmorpholine and in asolvent like dichloromethane. Reaction of the mixed anhydride withN,0-dimethyl hydroxylamine in presence of a base such asN-methylmorpholine and in a solvent such as dichloromethane gave theWeinreb amide 33. The amide 33 can be treated with lithium reagents ofgeneral formula R³Li or Grignard reagents of general formula R³MgBr in asolvent like tetrahydrofuran to give the fluoroketone 34.

SPECIFIC EXAMPLES

The following examples further illustrate the preparation of thecompounds of formula I. The examples are illustrative only and are notintended to limit the scope of the invention in any way. The followingabbreviations have the indicated meanings:

AcOH acetic acid EWG electron-withdrawing groups DIAD diisopropylazodicarboxylate TFAA trifluoroacetic anhydride r.t. room temperatureTHF tetrahydrofuran TFA trifluoroacetic acid DABCO1,4-diazabicyclo[2.2.2]octane EEDQN-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline DMFN,N-dimethylformamide DEAD diethyl azodicarboxylate mCPBAm-chloroperbenzoic acid Me CH₃ Ph phenyl tBu tert-butyl

Example 13-[4-[3-(tert-Butyldiphenylsilyloxy)propyl]phenoxy]-1-chloro-1,1-difluoro-2-propanone

3-(4-Hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane

A solution of 3-(4-hydroxyphenyl)-1-propanol (10.0 g, 66.0 mmol) andimidazole (6.7 g, 98.4 mmol) in N,N-dimethylformamide (50 ml) was cooledto 0-5° C. and treated dropwise with tert-butylchlorodiphenylsilane(21.5 g, 78.2 mmol). The resulting mixture was stirred at 0-5° C. for 2hours and then quenched by addition of water (400 ml) and toluene (500ml). The organic phase was washed with water, brine and dried overanhydrous magnesium sulfate. Evaporation of the solvent andchromatography of the residue on silica gel (elution toluene-ethylacetate, 95:5) gave 24.8 g (96%) of the title material as a clear oil.

Anal. Calcd. for C₂₅H₃₀O₂Si: C, 76.88; H, 7.74. Found: C, 76.74; H,7.67.

Methyl [4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]acetate

A solution of 3(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane(3.91 g, 10.0 mmol) and methyl bromoacetate (3.0 g, 19.7 mmol) inacetonitrile (100 ml) was treated with powdered anhydrous potassiumcarbonate (10 g) and the resulting mixture was heated under reflux for 1hour. The cooled mixture was filtered and the filtrate was concentratedin vacuo. Chromatography of the residue on silica gel (elutiontoluene-ethyl acetate, 98:2) gave 4.36 g (94%) of the title material asclear oil.

[4-[3-(tert-Butyldiphenylsilyloxy)propyl]phenoxy]acetic acid

A solution of methyl[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]acetate (4.36 g, 9.4mmol) in 80% aqueous ethanol (100 ml) was treated with potassiumhydroxide (2 g) and the resulting mixture was heated at 50° C. for 2hours. The solvent was then evaporated in vacuo. Ice water and ethylacetate were added and the aqueous phase was carefully adjusted to pHwith 1N hydrochloric acid. The organic phase was then washed with brine,dried (magnesium sulfate) and evaporated under reduced pressure to givea white solid. Recrystallization from hexane gave 3.41 g (81%) of thetitle acid as white crystals: mp 87-88° C.

3-[4-[3-(tert-Butyldiphenylsilyloxy)propyl]phenoxy]-1-chloro-1,1-difluoro-2-propanone

A solution of [4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]aceticacid (3.41 g, 7.6 mmol) in dichloromethane (30 ml) was treated withoxalyl chloride (0.96 g, 7.6 mmol) and a small drop ofN,N-dimethylformamide and the resulting solution was stirred at 22° C.for 1 hour. The solvent was then evaporated in vacuo and the residualoil was diluted with toluene (50 ml) and cooled to 0° C. This solutionwas treated with chlorodifluoroacetic anhydride (5.54 g, 22.8 mol)followed by pyridine (1.80 g, 22.8 mmol) added dropwise over 5 minutes.After 15 minutes at 0° C., the mixture was allowed to warm to 22° C. andstirred for 2 hours. The mixture was then cooled again to 0° C. andtreated dropwise with water (5 ml). After 10 minutes at 22° C., themixture was diluted with ethyl acetate, washed with saturated sodiumbicarbonate, brine and dried (magnesium sulfate). Evaporation of thesolvent and chromatography of the residue on silica gel (elutiontoluene-ethyl acetate, 9:1) gave 1.02 g (26%) of the title material as alight yellow oil.

Anal. Calcd. for C₂₈H₃₁ClF₂O₃Si.0.6 H₂O: C, 63.71; H, 6.15. Found: C,63.76; H, 6.23.

Example 23-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-propanone

3-[4-[3-(tert-Butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanol

A mixture of 1,2-epoxy-3-[4-(tert-butoxycarbonyl)phenoxy]propane (5.11g, 20.4 mmol) [S. P. Connors, et al., J. Med. Chem., 1991, 34, 1570] and3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (7.97 g, 20.4mmol) in N,N-dimethylformamide (50 ml) was treated with1,4-diazabicyclo[2,2,2]octane (0.45 g) and the resulting mixture washeated at 70° C. for 48 hours. The cooled mixture was diluted with ethylacetate, washed with water, saturated sodium bicarbonate and dried(magnesium sulfate). Evaporation of the solvent and chromatography ofthe residue on silica gel (elution toluene-ethyl acetate, 95:5) gave7.67 g (58%) of the title material as oil.

Anal. Calcd. for C₃₉H₄₈O₆Si: C, 73.09; H, 7.55. Found: C, 73.01; H,7.47.

3-[4-[3-(tert-Butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone

A solution of3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanol (2.08 g, 3.25 mmol) in dichloromethane (120ml) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (5.46 g, 12.9 mmol) and the resulting mixture was stirredat 22° C. for 18 hours. The reaction mixture was then diluted with ethylacetate, washed with 10% aqueous sodium thiosulfate, saturated sodiumbicarbonate, brine and dried (magnesium sulfate). Evaporation of thesolvent and chromatography of the residue on silica gel (elutiontoluene-ethyl acetate, 95:5) gave 1.82 g (88%) of the title material asoil.

Anal. Calcd. for C₃₉H₄₆O₆Si: C, 73.32; H, 7.26. Found: C, 73.36; H,7.19.

3-[4-(3-Hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone

A solution of methyl3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone(1.44 g, 2.25 mmol) in tetrahydrofuran (35 ml) was treated at 22° C.with acetic acid (0.8 ml) followed by 5 ml (5 mmol) of a 1M solution oftetrabutylammonium fluoride in tetrahydrofuran. The mixture was thenheated at 70° C. for 4 hours. The cooled reaction mixture was thendiluted with ethyl acetate, washed with water, saturated sodiumbicarbonate, brine and dried (magnesium sulfate). Evaporation of thesolvent and chromatography of the residue on silica gel (elutiontoluene-ethyl acetate, 7:3) gave 0.88 g (97%) of the title material asoil.

Anal. Calcd. for C₂₃H₂₈O₆: C, 68.98; H, 7.05. Found: C, 69.34; H, 6.70.

3-[4-(3-Methanesulfonyloxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone

A solution of3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonly)phenoxy]-2-propanone(0.70 g, 0.75 mmol) in dichloromethane (10 ml) was cooled to 0° C. andtreated with triethylamine (0.51 ml, 3.66 mmol) followed bymethanesulfonyl chloride (0.23 ml, 2.97 mmol) added dropwise over 5minutes. After 1 hour at 0° C., the reaction mixture was quenched by theaddition of water and ethyl acetate. The organic phase was washed withwater, brine and dried (magnesium sulfate). Evaporation of the solventand chromatography of the residue on silica gel (elution toluene-ethylacetate, 8:2) gave 0.66 g, (79%) of the title material as oil.

Anal. Calcd. for C₂₄H₃₀O₈S.0.3 H₂O: C, 59.56; H, 6.37; S, 6.63. Found:C, 59.54; H, 6.35; S, 7.07.

3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone

A mixture of3-[4-(3-methanesulfonyloxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone(0.520 g, 1.09 mmol), N-methyl-2-bis-(4-chlorophenyl)ethylamine[Maryanoff, et al., J. Med. Chem. (1984) 27, 1067-1071] (0.76 g, 2.71mmol) and sodium iodide (0.012 g) in acetonitrile (10 ml) was heated at70° C. for 20 hours. The cooled mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate, brine and dried (magnesiumsulfate). Evaporation of the solvent and chromatography of the residueon silica gel (elution toluene-ethyl acetate, 8:2) gave 0.57 g (79%) ofthe title material as syrup.

Anal. Calcd. for C₃₈H₄₁Cl₂NO₅.0.7 H₂O: C, 67.59; H, 6.33; N, 2.07.Found: C, 67.59; H, 6.25; N, 2.10.

3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-propanone

3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone(2.51 g, 3.79 mmol) was dissolved in 15 ml of 1M solution of hydrogenchloride in acetic acid and the resulting mixture was stirred at 22° C.for 1.5 hours. The solvent was then evaporated in vacuo and a mixture ofwater and dichloromethane was added. The pH of the aqueous phase wasadjusted to 4.5 with diluted sodium hydroxide and the two phases werestirred for 5 minutes. The organic phase was collected, washed withbrine and dried (magnesium sulfate). Evaporation of the solvent andchromatography of the residue on silica gel (elution ethylacetate-methanol 0-5%) gave 1.29 g (56%) of the title material as oil.The hydrochloride salt was prepared and obtained as a foam.

Anal. Calcd. for C₃₄H₃₃Cl₂NO₅.HCl.H₂O: C, 61.78; H, 5.49; N, 2.12.Found: C, 61.85; H, 5.21; N, 2.15.

Example 3 (3R and3S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-butanone

Trans-4-[4-(tert-butoxycarbonyl)phenoxy]-2-butene

A solution of 1,1-dimethylethyl 4-hydroxybenzoate (3.68 g, 18.9 mol) and2-buten-1-ol (1.37 g, 18.9 mol) in dry benzene (100 ml) at 22° C. wastreated with triphenylphosphine (5.48 g, 20.9 mmol) followed by asolution of diisopropyl azodicarboxylate (4.22 g, 20.9 mmol) in drybenzene (10 ml) added dropwise over 7 minutes. After 3 hours at 22° C.,the solvent was concentrated under reduced pressure and the residue waschromatographed on silica gel. Elution with a mixture of toluene andethyl acetate (99:1) gave 3.70 g (79%) of the title material as a clearoil: bp 85-90° C./0.1 torr (bulb to bulb, air bath temperature).

Anal. Calcd. for C₁₅H₂₀O₃: C, 72.55; H, 8.12. Found: C, 72.44; H, 8.27.

2,3-Epoxy-4-[4-(tert-butoxycarbonyl)phenoxy]butane

A solution of trans-4-[4-(tert-butoxycarbonyl)phenoxy]-2-butene (3.10 g,12.48 mmol) in dry dichloromethane (50 ml) was treated at 22° C. with3-chloroperoxybenzoic acid (4.30 g, 24.9 mmol) and the resulting mixturewas stirred at 22° C. for 18 hours. The mixture was then diluted withtoluene, washed with 5% sodium thiosulfate, saturated sodium bicarbonateand brine. After drying (sodium sulfate), evaporation of the solventgave an oil that was chromatographed on silica gel. Elution with amixture of toluene and ethyl acetate (95:5) gave 3.16 g (96%) of thetitle material as an oil which solidified upon standing: bp 85-90°C./0.05 torr (bulb to bulb, air bath temperature); mp 47-48° C.

Anal. Calcd. for C₁₅H₂₀O₄: C, 68.16; H, 7.63. Found: C, 67.91; H, 7.30.

Erythro-3-[4-(3-tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanol

A mixture of 2,3-epoxy-4-[4-(tert-butoxycarbonyl)phenoxy]butane (0.656g, 2.48 mmol) and 3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (0.970 g, 2.48 mmol) in dry N,N-dimethylformamide (10 ml) wastreated with 1,4-diazabicyclo[2,2,2]octane (0.060 g) and the resultingmixture was stirred at 70° C. for 72 hours. The reaction mixture wasthen diluted with ethyl acetate, washed with water, saturated sodiumbicarbonate and brine. After drying (anhydrous magnesium sulfate),evaporation of the solvent gave an oil that was chromatographed onsilica gel. Elution with a mixture of toluene and ethyl acetate (98:5)gave 0.206 g (12%) of the title material as an oil.

Anal. Calcd. for C₄₀H₅₀O₆Si: C, 73.36; H, 7.70. Found: C, 73.42; H,7.64.

(3R and3S)-3-[4-[3-tert-Butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone

A solution oferythro-3-[4-(3-tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanol(0.150 g, 0.23 mmol) in dry dichloromethane (10 ml) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (0.38 g, 0.91 mol) and the resulting mixture was stirred at22° C. for 18 hours. The reaction mixture was then diluted with ethylacetate, washed with 5% sodium thiosulfate, saturated sodium bicarbonateand brine. After drying (anhydrous sodium sulfate), evaporation of thesolvent gave an oil that was chromatographed on silica gel. Elution witha mixture of toluene and ethyl acetate (95:5) gave 0.130 g (87%) of thetitle material as an oil.

Anal. Calcd. for C₄₀H₄₈O₆Si: C, 72.98; H, 7.44. Found: C, 72.96; H,7.67.

(3R and3S)-3-[4-(3-Hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone

A solution of (3R and3S)-3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone(0.314 g, 0.48 mmol) in tetrahydrofuran (10 ml) was treated with aceticacid (0.7 ml) followed with 1M tetrabutylammonium fluoride intetrahydrofuran (1.1 ml, 1.1 mmol). The resulting mixture was thenheated at 70° C. for 3.5 hours. The cooled mixture was diluted withethyl acetate, washed with saturated sodium bicarbonate, brine and dried(magnesium sulfate). Evaporation of the solvent and chromatography ofthe residue on silica gel (elution toluene-ethyl acetate, 8:2) gave0.106 g (53%) of the title material as a syrup.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.58 (9H, s, t-Bu), 1.61 (3H, d, J=7.2Hz, CH₃), 1.89, (2H, m, CH₂), 2.69 (2H, m, CH₂), 3.68 (2H, m, CH₂O), 4.9and 5.13 (2×1H, 2d, J=17.8 Hz, OCH₂), 4.91 (1H, m, CH), 6.81 and 7.91(2×2H, 2d, J=8.9 Hz, aromatics) and 6.86 and 7.16 (2×2H, 2d, J=8.62 Hz,aromatics).

MS (ESI⁺) (m/z): 415 (MH⁺).

(3R and3S)-3-[4-(3-Methanesulfonyloxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone

A solution of (3R and3S)-3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone(0.092 g, 0.22 mmol) in dry dichloromethane (5 ml) was cooled to 0° C.and treated with triethylamine (0.07 ml, 0.5 mmol) followed bymethanesulfonyl chloride (0.03 ml, 0.39 mmol). After 45 minutes at 0°C., the reaction mixture was quenched by addition of ethyl acetate (100ml) and water. The organic phase was washed with saturated sodiumbicarbonate, brine and dried (magnesium sulfate). Evaporation andchromatography of the residue on silica gel (elution toluene and ethylacetate, 9:1) gave 0.090 g (82%) of the title material as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.58 (9H, s, t-Bu), 1.61 (3H, d, J=7.3Hz, CH₃), 2.06 (2H, m, CH₂), 2.72 (2H, m, CH₂), 3.02 (3H, s, OMs), 4.24(2H, t, J=6.1 Hz, CH₂O), 4.90 and 5.13 (2×1H, 2d, J=18.2 Hz, OCH₂), 4.92(1H, q, J=7.3 Hz, CH), 6.84 and 7.92 (2×2H, 2d, J=8.6 Hz, aromatics),6.86 and 7.15 (2×2H, 2d, J=8.6 Hz, aromatics).

MS (ESI⁺) (m/z): 510 (M+NH₄ ⁺).

(3R and3S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone

A solution of (3R and3S)-3-[4-(3-methanesulfonyloxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone(0.080 g, 0.162 mmol) and N-methyl-2-bis-(4-chlorophenyl)ethylamine(0.050 g, 0.178 mml) in acetonitrile (5 ml) was treated withN,N-diisopropylethylamine (0.035 ml) and sodium iodide (0.005 g) and theresulting mixture was stirred at 80° C. for 16 hours. The cooled mixturewas diluted with ethyl acetate, washed with saturated sodiumbicarbonate, brine and dried (magnesium sulfate). Evaporation of thesolvent and chromatography of the residue on silica gel (elution tolueneand ethyl acetate, 85:15) gave 0.096 g (87%) of the title material as asyrup.

¹H NMR 400 MHz (C₆D₆) δ (ppm): 1.19 (2H, d, J=7.3 Hz, CH₃), 1.49 (9H, s,t-Bu), 1.56 (2H, m, CH₂), 2.02 (3H, s, NCH₃), 2.19 (2H, t, J=6.9 Hz,CH₂) 2.35 (2H, t, J=8.1 Hz, CH₂), 2.58 (2H, d, J=7.7 Hz, NCH₂), 3.81(1H, t, J=7.7 Hz, CH), 4.47 and 4.61 (2×1H, 2d, J=17.4 Hz, OCH₂), 4.51(1H, q, J=7.3 Hz, CH), 6.63 and 6.87 (2×2H, 2d, J=8.5 Hz, aromatics),6.73 and 8.68 (2×2H, 2d, J=8.7 Hz, aromatics), 6.79 and 7.14 (2×4H, 2d,J=8.0 Hz, aromatics).

MS (ESI) (m/z⁺): 676 (MH⁺).

(3R and3S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl)phenoxy]-1-(4-carboxyphenoxy)-2-butanone

(3R and3S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone(0.084 g, 0.12 mmol) was treated at 22° C. with 2 ml of 1M hydrochloricacid in acetic acid. After 1.5 hours, the solvent was evaporated invacuo and the residue was partitioned between dichloromethane (10 ml)and water (10 ml). The pH of the aqueous phase was adjusted to 4.5 with0.1N sodium hydroxide and the aqueous phase was extracted twice withdichloromethane. The combined organic extracts were dried (magnesiumsulfate) and concentrated. Chromatography of the residue on silica gel(elution ethyl acetate-methanol, 0-20%) gave 0.032 g (41%) of the titlematerial as a foam. The hydrochloride salt was prepared and obtained asan amorphous solid.

Hydrochloride salt: ¹H NMR 400 MHz (DMSO-d₆) δ (ppm): 1.5 (3H, d, J=6.8,Hz, CH₃), 1.9 (2H, m, CH₂), 2.74 (3H, s, NCH₃), 2.95-3.07 (2H, m, CH₂),3.76-4.03 (2H, m, CH₂), 4.66 (1H, broad t, J=7.3 Hz, CH), 5.14 and 5.37(2×1H, 2d, J=18.3 Hz, OCH₂), 5.18 (1H, q, J=6.8 Hz, CH), 6.92 and 7.12(2×2H, 2d, J=8.5 Hz, aromatics), 6.96 and 7.86 (2×2H, 2d, J=8.8 Hz,aromatics) and 7.4-7.5 (8H, m, aromatics).

MS (ESI⁺) m/z: 620 (MH⁺).

Example 4 (3R and3S)-1-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-3-(4-carboxyphenoxy)-2-butanone

(3R and 3S)-3-[4-(tert-Butoxycarbonyl)phenoxy]-1-butene

A solution of 1,1-dimethylethyl 4-hydroxybenzoate (5.0 g, 25.7 mmol) inN,N-dimethylformamide (35 ml) was treated with a solution of sodiumhydroxide (1.14 g, 35.1 mmol) in water (2 mL). Then 3-chloro-1-butene(3.06 g, 33.8 mmol) was added and the resulting mixture was heated at45° C. for 5 hours. The cooled mixture was diluted with toluene, washedwith water, dried (magnesium sulfate) and concentrated under reducedpressure. Chromatography of the residue on silica gel (elutiontoluene-hexane, 1:1) gave 3.84 g (60%) of the title material as a clearoil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.47 (3H, d, J=6.4 Hz, CH₃), 1.59 (9H,s, t-Bu), 4.98 (1H, m, CH), 5.2-5.3 (2H, m, olefinic C—H), 5.85-5.95(1H, m, olefinic C—H), 6.90 and 7.92 (2×2H, 2d, J=8.9 H, aromatic).

Anal. Calcd. for C₁₅H₂₀O₃: C, 72.55; H, 8.12. Found: C, 72.30; H, 8.17.

(2R, 2S and 3R, 3S)-1,2-Epoxy-3-[4-(tert-butoxycarbonyl)phenoxy]-butane

A solution of (3R and 3S)-3-[4-(tert-butoxycarbonyl)phenoxy]-1-butene(3.78 g, 15.2 mmol) in dry dichloromethane (50 ml) was treated at 22° C.with 3-chloroperoxybenzoic acid (4.8 g, 28.0 mmol) and the resultingmixture was stirred for 140 hours. The mixture was then diluted withtoluene, washed with 5% sodium thiosulfate, sodium bicarbonate and dried(magnesium sulfate). Evaporation of the solvent and chromatography ofthe residue on silica gel (elution toluene-ethyl acetate 2%) gave 3.53 g(87%) of the title material as an oil. ¹H NMR indicated a 6:4diastereoisomeric mixture which was used as such for the next step.

(2R, 2S and 3R,3S)-1-[4-[3-tert-Butyldiphenylsilyloxy)propyl]phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanol

A solution of (2R, 2S and 3R,3S)-1,2-epoxy-3-[4-(tert-butoxycarbonyl)phenoxy]-butane (3.46 g, 13.1mmol) and 3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy) propane(5.11 g, 13.1 mmol) in dry N,N-dimethylformamide (35 ml) was treatedwith 1,4-diazabicyclo[2,2,2]octane (0.4 g) and the resulting mixture washeated at 80° C. for 36 hours. The reaction mixture was then dilutedwith ethyl acetate, washed with water, saturated sodium bicarbonate andbrine. After drying (anhydrous magnesium sulfate), evaporation of thesolvent gave an oil that was chromatographed on silica gel. Elution witha mixture of hexane and ethyl acetate (85:15) gave 3.27 g (38%) of thetitle material as an oil. ¹H NMR indicated a 6:4 diastereoisomericmixture that was used as such for the next step.

(3R and3S)-1-[4-[3-tert-Butyldiphenylsilyloxy)propyl]phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone

A solution of (2R, 2S and 3R,3S)-1-[4-[3-tert-butyldiphenylsilyloxy)propyl]phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanol(3.22 g, 4.9 mmol) in dry dichloromethane (180 ml) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (8.27 g, 19.5 mol) and the resulting mixture was stirred at22° C. for 16 hours. The reaction mixture was then washed with 5% sodiumthiosulfate, saturated sodium bicarbonate and brine. After drying(magnesium sulfate), evaporation of the solvent gave an oil that waschromatographed on silica gel. Elution with a mixture of toluene andethyl acetate (95:5) gave 3.10 g (96%) of the title material as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.07 (9H, s, Sit-Bu), 1.59 (9H, s,t-Bu), 1.64 (3H, d, J=7.3 Hz, CH₃), 1.83 (2H, m, CH₂), 2.66 (2H, m,CH₂), 3.68 (3H, t, J=6.05 Hz, OCH₂), 4.76 and 4.98 (2×1H, 2d, J=17.7 Hz,OCH₂), 4.76 and 4.98 (2×1H, 2d, J=17.7 Hz, OCH₂), 5.09 (1H, q, J=7.3 H,CH), 6.78 (2H, d, J=8.6 Hz, aromatic), 6.90 (2H, d, J=8.6 Hz, aromatic),7.08 (2H, d, J=8.6 Hz, aromatic), 7.42 (6H, m, aromatic), 7.68 (4H, m,aromatic) and 7.96 (2H, d, J=8.6 Hz, aromatic).

Anal. Calcd. for C₄₀H₄₈O₆Si: C, 73.59; H, 7.41. Found: C, 73.25; H,7.50.

(3R and3S)-1-[4-(3-Hydroxypropyl)phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone

A solution of (3R and3S)-1-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone(2.82 g, 4.32 mmol) in tetrahydrofuran (70 ml) was treated with aceticacid (1.5 ml) followed by 1M tetrabutylammonium fluoride intetrahydrofuran (10 ml, 10.0 mmol). The mixture was then heated at 70°C. for 3.5 hours. The cooled mixture was then diluted with ethylacetate, washed with saturated sodium bicarbonate, brine and dried(magnesium sulfate). Evaporation of the solvent and chromatography ofthe residue on silica gel (elution toluene-ethyl acetate 8:2) gave 1.64g (91%) of the title material as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.59 (9H, s, t-Bu), 1.64 (2H, d, J=7.3Hz, CH₃), 1.87, (2H, m, CH₂), 2.67 (2H, t, J=7.7 Hz, CH₂), 3.67 (2H, t,J=6.3 Hz, OCH₂), 4.77 and 4.98 (2×1H, 2d, J=17.7 Hz, OCH₂), 5.08 (1H, q,J=7.3 Hz, CH), 6.80 (2H, d, J=8.7 Hz, aromatic) 6.88 (2H, d, J=8.5 Hz,aromatic), 7.12 (2H, d, J=8.7 Hz, aromatic) and 7.95 (2H, d, J=8.5 Hz,aromatic).

Anal. Calcd. for C₂₄H₃₀O₆.0.3H₂O: C, 68.65; H, 7.35. Found: C, 68.60; H,7.27.

(3R and3S)-1-[4-(3-Methanesulfonyloxypropyl)phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone

A solution of (3R and3S)-1-[4-(3-hydroxypropyl)phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone(1.57 g, 3.8 mmol) in dry dichloromethane (25 ml) was cooled to 0-50° C.and treated with triethylamine (1.1 ml, 7.9 mmol) followed bymethanesulfonyl chloride (0.5 mL, 6.46 mmol) added dropwise over 2minutes. After 45 minutes at 0-5° C., the reaction mixture was quenchedby addition of ethyl acetate and saturated sodium bicarbonate. Theorganic phase was washed with brine and dried (anhydrous magnesiumsulfate) and evaporated. Chromatography of the residual oil on silicagel (elution toluene-ethyl acetate, 9:1) gave 1.83 g (97%) of the titlematerial as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.59 (9H, s, t-Bu), 1.64 (3H, d, J=6.9Hz, CH₃), 2.71 (2H, t, J=7.3 Hz, CH₂), 3.01 (3H, s, OMs), 4.22 (2H, t,J=6.04 Hz, OCH₂), 4.77 and 5.01 (2×1H, 2d, J=17.9 Hz, OCH₂), 5.07 (1H,q, J=6.9 Hz, CH), 6.81 (2H, d, J=8.7 Hz, aromatic), 6.90 (2H, d, J=8.5Hz, aromatic), 7.11 (2H, d, J=8.7 Hz, aromatic) and 7.96 (2H, d, J=8.5Hz, aromatic).

Anal. Calcd. for C₂₅H₃₂O₈S.H₂O: C, 58.81; H, 6.71; S, 6.28. Found: C,58.80; H, 6.31; S, 6.01.

(3R and3S)-1-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone

A solution of (3R and3S)-1-[4-(3-methanesulfonyloxypropyl)phenoxy]-3-[4-tert-butoxycarbonyl)phenoxy]-2-butanone(1.67 g, 3.39 mmol) and N-methyl-2-bis-(4-chlorophenyl)ethylamine (0.98g, 3.49 mml) in acetonitrile was treated with N,N-diisopropylethylamine(0.74 ml, 4.26 mol) and sodium iodide (0.040 g) and the resultingmixture was heated at 80° C. for 20 hours. The cooled mixture wasdiluted with ethyl acetate, washed with saturated sodium bicarbonate,brine and dried (magnesium sulfate). Evaporation of the solvent andchromatography of the residue on silica gel (elution toluene and ethylacetate, 85:15) gave 1.85 g (90%) of the title material as a clearsyrup.

¹H NMR 400 MHz (C₆D₆) δ (ppm): 1.16 (3H, d, J=6.4 Hz, CH₃), 1.50 (9H s,t-Bu), 1.55 (2H, m, CH₂), 2.01 (3H, s, NCH₃), 2.18 (2H, t, J=6.9 Hz,CH₂), 2.34 (2H, t, J=7.5 Hz, CH₂), 2.58 (2H, d, J=7.5 Hz, CH₂), 3.80(1H, t, J=7.5 Hz, CH), 4.45 and 4.59 (2×1H, 2d, J=17.6 Hz, OCH₂), 4.53(1H, q, J=6.4 Hz, CH), 6.61 (2H, 2d, J=8.7 Hz, aromatic), 6.77 (2H, d,J=9.0 Hz, aromatics), 6.79 (4H, J=8.6 Hz, aromatic), 6.87 (2H, d, J=8.7Hz, aromatic), 7.14 (4H, d, J=8.6 Hz, aromatic) and 8.09 (2H, d, J=9.0Hz, aromatic).

Anal. Calcd. for C₃₉H₄₃Cl₂NO₅.1.4H₂O: C, 66.74; H, 6.58; S, 2.00. Found:C, 66.60; H, 6.84; S, 2.11.

(3R and3S)-1-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-3-(4-carboxyphenoxy)-2-butanone

(3R and4S)-1-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone(1.77 g, 2.62 mmol) was dissolved in 1M hydrochloric acid in acetic acid(15 ml) and the resulting mixture was stirred at 22° C. for 1.5 hours.The acetic acid was then evaporated and the residue was partitionedbetween dichloromethane and water. The pH of the aqueous phase wasadjusted to 4.5 with 0.1N sodium hydroxide and the aqueous phase wasextracted twice with dichloromethane. The combined organic extracts weredried (magnesium sulfate) and concentrated. Chromatography of theresidue on silica gel (elution ethyl acetate-methanol 0-10%) gave 0.829g (51%) of the title material as a foam. The hydrochloride salt wasprepared and obtained as an amorphous solid.

Hydrochloride salt: ¹H NMR 400 MHz (DMSO-d₆) δ (ppm): 1.53 (3H, d,J=6.55 Hz, CH₃), 1.9 (2H, m, CH₂), 2.73 (3H, broad, NCH₃), 3.05 (2H, m,CH₂), 3.78 and 3.98 (2×1H, 2m, CH₂), 4.64 (1H, t, J=7.3 Hz, CH), 5.03and 5.23 (2×1H, 2d, J=18.4 Hz, OCH₂), 5.34 (1H, q, J=6.55 Hz, CH), 6.84(2H, d, J=8.3 Hz, aromatic), 7.04 (2H, d, J=8.8 Hz, aromatic), 7.08 (2H,d, J=8.3 Hz, aromatic) 7.4 (8H, m, aromatic) and 7.86 (2H, d, J=8.8 Hz,aromatic).

Anal. Calcd. for C₃₅H₃₅Cl₂NO₅.HCl.H₂O: C, 62.27; H, 5.67; S, 2.07.Found: C, 62.34; H, 5.57; S, 2.23.

Example 53-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-3-methyl-2-butanone

Methyl 2-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-2-methylpropionate

A solution of 3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane(5.00 g, 12.8 mmol) and methyl 2-bromo-2-methylpropionate (4.53 g, 25.0mmol) in dry acetonitrile (25 ml) was treated with cesium carbonate (8.3g, 25.4 mmol) and the resulting mixture was heated at 60° C. for 3.5hours. The cooled mixture was diluted with ethyl acetate, washed withwater, brine and dried (magnesium sulfate). Evaporation of the solventand chromatography of the residue on silica gel (elution toluene) gave5.88 g (93%) of the title material as a clear oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.08 (9H, s, t-Bu) 1.59 (6H, s, CH₃),1.86 (2H, m, CH₂), 2.67 (2H, t, J=7.91 Hz, CH₂), 3.69 (2H, t, J=6.21 Hz,OCH₂), 3.80 (3H, s, OCH₃), 6.76 (2H, t, J=8.6 Hz, aromatic), 7.05 (2H,d, J=8.6 Hz, aromatic), 7.4 and 7.7 (6H and 4H, 2m, aromatic).

Anal. Calcd. for C₃₀H₃₈O₄Si: C, 73.43; H, 7.81. Found: C, 73.5; H, 7.96.

2-[4-[3-(tert-Butyldiphenylsilyloxy)propyl]phenoxy]-2-methylpropanol

A solution of methyl2-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-2-methylpropionate(5.88 g, 11.98 mmol) in diethyl ether (100 ml) was treated at 22° C.with 23 ml (23 mmol) of a 1M solution of lithium aluminum hydride inether. The resulting mixture was then heated under reflux for 1 hour.The cooled mixture was quenched by addition of ethyl acetate, water (5ml) and 1N sodium hydroxide (5 ml). The solid formed was filtered andthe filtrate was evaporated and purified on silica gel. Elution with amixture of toluene and ethyl acetate (9:1) gave 5.14 g (93%) of thetitle material as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.08 (9H, s, t-Bu) 1.27 (6H, s, CH₃),1.87 (2H, m, CH₂), 2.22 (1H, t, J=6.67 Hz, OH), 2.70 (2H, t, J=7.5 Hz,CH₂), 3.59 (2H, d, J=6.67, CH₂OH), 3.69 (2H, d, J=6.3 Hz, OCH₂), 6.89(2H, d, J=8.2 Hz, aromatic), 7.08 (2H, d, J=8.2 Hz, aromatic), 7.4 and7.7 (6H and 4H, 2m, aromatic).

Anal. Calcd. for C₂₉H₃₈O₃Si: C, 75.28; H, 8.28. Found: C, 74.60; H,8.28.

2-[4-[3-(tert-Butyldiphenyisilyloxy)propyl]phenoxy]-2-methylpropionaldehyde

A solution of2-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-2-methyl propanol(5.14 g, 11.1 mmol) in dry dichloromethane (150 ml) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodi-nane) (19.2 g, 45.3 mmol) and the resulting mixture was stirredat 22° C. for 3 hours. The reaction mixture was then diluted with ethylacetate, washed with 5% sodium thiosulfate, saturated sodiumbicarbonate, brine and dried (magnesium sulfate). Evaporation of thesolvent and chromatography of the residue on silica gel (elution tolueneethyl acetate, 99:1) gave 3.25 g (63%) of the title material as a clearoil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.07 (9H, s, t-Bu) 1.42 (6H, s, CH₃),1.85 (2H, m, CH₂), 2.67 (2H, broad t, J=7.8 Hz, CH₂), 3.68 (3H, t, J=6.4Hz, OCH₂), 6.77 (2H, d, J=8.7 Hz, aromatic), 7.05 (2H, d, J=8.7 Hz,aromatic), 7.4 and 7.68 (6H and 4H, 2m, aromatic) and 9.87 (1H, s, CHO).

Anal. Calcd. for C₂₉H₃₆O₃Si: C, 75.61; H, 7.88. Found: C, 75.67; H,7.85.

(2R and2S)-3-[4-[3-tert-Butyldiphenylsilyloxy)propyl]phenoxy]-1,2epoxy-3-methylbutane

To a mixture of sodium hydride (0.40 g of 60% in mineral oil, 10.0 mmol)and trimethylsulfoxonium iodide (2.18 g, 9.9 mol) under nitrogen wasadded dropwise 30 ml of dimethylsulfoxide. After 30 minutes at 22° C., asolution of2-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-2-methylpropionaldehyde(3.05 g, 6.62 mmol) in dry dimethylsulfoxide (30 ml) was added over 5minutes and the resulting mixture was stirred at 22° C. for 30 minutes.The reaction mixture was then quenched by addition of water and ethylacetate. The organic phase was washed with water, brine and dried.Evaporation of the solvent and chromatography of the residue on silicagel (elution toluene-ethyl acetate, 98:2) gave 2.66 g (84%) of the titlematerial as a clear oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.08 (9H, s, t-Bu), 1.28 and 1.29 (2×3H,2s, CH₃), 1.87 (2H, m, CH₂), 2.7 (3H, m, CH₂ and CH of oxirane), 2.81(1H, broad t, CH of oxirane), 3.19 (1H, m, CH of oxirane), 3.70 (2H, t,J=6.8, OCH₂), 6.95 (2H, d, J=8.7 Hz, aromatic), 7.08 (2H, d, J=8.7 Hz,aromatic), 7.4 and 7.69 (6H and 4H, 2m, aromatic).

Anal. Calcd. for C₃₀H₄₈O₃Si: C, 75.90; H, 8.07. Found: C, 75.44; H,8.06.

(2R and3S)-3-[4-[3-(tert-Butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanol

A mixture of (2R and2S)-3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1,2epoxy-3-methylbutane(2.58 g, 5.43 mmol) and 1,1-methylethyl 4-hydroxybenzoate (1.07 g, 5.51mmol) in dry N,N-dimethylformamide (20 mL) was treated with1,4-diazabicyclo[2,2,2] octane (0.20 g) and the resulting solution wasstirred at 80° C. for 72 hours. Additional amounts of base (2×0.2 g)were added after 24 and 48 hours. The reaction mixture was then quenchedby addition of water and ethyl acetate. The organic phase was washedwith brine, dried (magnesium sulfate) and concentrated. The residue waschromatographed on silica gel (elution toluene-ethyl acetate, 95:5) togive 0.618 g (17%) of the title material as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.09 (9H, s, t-Bu), 1.34 and 1.35 (2×3H,2s, CH₃), 1.61 (9H, s, t-Bu), 1.9 (2H, m, CH₂), 2.71 (2H, broad t, CH₂),3.70 (2H, t, J=6.1 Hz, OCH₂), 4.11 (1H, dd, J=3.3 and J=7.33 Hz, CH),4.18 (1H, dd, J=7.33 and J=9.6 Hz, CH), 4.37 (1H, dd, J=3.17 and J=9.6Hz, CH), 6.91 (2H, d, J=8.6 Hz, aromatic), 6.98 (2H, d, J=9.0 Hz,aromatic), 7.10 (2H, d, J=8.6 Hz, aromatic), 7.4 and 7.7 (6H and 4H, 2m,aromatic), 7.97 (2H, d, J=9.0 Hz, aromatic).

3-[4-[3-(tert-Butyldiphenyisilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone

A solution of (2R and2S)-3-[4-[3-(tert-butyldiphenysilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanol(0.60 g, 0.89 mmol) in dry dichloromethane (30 ml) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (1.50 g, 3.57 mmol) and the resulting mixture was stirredat 22° C. for 3 hours. The reaction mixture was diluted with ethylacetate, washed with 5% sodium thiosulfate, saturated sodium bicarbonateand brine. After drying (magnesium sulfate), the organic phase wasconcentrated and chromatographed on silica gel. Elution with a mixtureof toluene and ethyl acetate (98:2) gave 0.587 g (98%) of the titlematerial as a clear oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.09 (9H, s, t-Bu), 1.54 (6H, s, 2×CH₃),1.60 (9H, s, t-Bu), 1.87 (2H, m, CH₂), 2.71 (2H, broad t, CH₂), 3.70(2H, t, J=6.3 Hz, OCH₂), 5.26 (2H, s, OCH₂), 6.82 (2H, d, J=8.5 Hz,aromatic), 6.92 (2H, d, J=8.5 Hz, aromatic), 7.11 (2H, d, J=8.5 Hz,aromatic), 7.4 and 7.7 (6H and 4H, 2m, aromatic), and 7.95 (2H, d, J=8.5Hz, aromatic).

3-[4-[3-Hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone

A solution of3-[4-[3-(tert-butyldiphenylsilyloxy))propyl]phenoxy]-1-[4-tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone(0.562 g, 0.84 mmol) in tetrahydrofuran (20 ml) was treated with aceticacid (0.3 ml) followed with 2 ml (2.0 mmol) of 1 M tetrabutylammoniumfluoride in tetrahydrofuran. The mixture was then heated at 70° C. for3.5 hours. The cooled mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate, brine and dried (magnesium sulfate).Evaporation of the solvent and chromatography of the residue on silicagel (elution toluene-ethyl acetate, 8:2) gave 0.333 g (92%) of the titlematerial as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.55 (6H, s, 2×CH₃), 1.60 (9H, s, t-Bu),1.9 (2H, m, CH₂), 2.70 (2H, broad t, CH₂), 3.70 (3H, t, J=6.2 Hz, OCH₂),5.25 (2H, s, OCH₂), 6.85 (2H, d, J=8.5 Hz, aromatic), 6.91 (2H, d, J=8.9Hz, aromatic), 7.15 (2H, d, J=8.5 Hz, aromatic) and 7.95 (2H, d, J=8.9Hz, aromatic).

3-[4-(3-Methanesulfonyloxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone

A solution of3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone(0.312 g, 0.73 mmol) in dry dichloromethane (15 ml) was cooled to 0-5°C. and treated with triethylamine (0.23 ml, 1.65 mmol) followed withmethanesulfonyl chloride (0.10 ml, 1.29 mmol) added dropwise over 2minutes. The reaction mixture was stirred at 0° C. for 45 minutes andthen quenched by the addition of ethyl acetate and water. The organicphase was washed with brine, dried (magnesium sulfate) and concentrated.The residue was chromatographed on silica gel (elution toluene-ethylacetate, 85:15) to give 0.369 g (100%) of the title material as a clearoil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.55 (6H, s, 2×CH₃), 1.60 (9H, s, t-Bu),2.08 (2H, m, CH₂), 2.74 (2H, broad t, J=7.5 Hz, CH₂), 3.03 (3H, s, Ms),4.25 (2H, t, J=6.3 Hz, OCH₂), 5.24 (2H, s, OCH₂), 6.87 (2H, d, J=8.6 Hz,aromatic), 6.91 (2H, d, J=9.1 Hz, aromatic), 7.14 (2H, d, J=8.6 Hz,aromatic), and 7.95 (2H, d, J=9.1 Hz, aromatic).

MS (ESI⁺) (m/z): 524 (M+NH₄ ⁺).

3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone

A solution of3-[4-(3-methanesulfonyloxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone (0.342 g, 0.67 mmol) andN-methyl-2-bis-(4-chlorophenyl)ethylamine (0.21 g, 0.74 mol) inacetonitrile (10 ml) was treated with N,N-diisopropylethylamine (0.15ml) and sodium iodide (0.020 g) and the resulting mixture was heated at80° C. for 20 hours. The cooled mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate, brine and dried (magnesiumsulfate). Evaporation of the solvent and chromatography of the residueon silica gel (elution toluene-ethyl acetate, 85:15) gave 0.425 (91%) ofthe title material as an oil.

¹H NMR 400 MHz (C₆D₆) δ (ppm): 1.35 (6H, s, 2×CH₃), 1.60 (9H, s, t-Bu)1.65 (2H, m, CH₂), 2.11 (3H, s, NCH₃), 2.28 (2H, t, J=6.8 Hz, CH₂), 2.43(2H, t, J=7.6 Hz, CH₂), 2.67 (2H, d, J=8.2 Hz, CH₂), 3.90 (1H, t, J=8.2Hz, CH), 5.04 (2H, s, OCH₂), 6.9 (10H, m, aromatic), 7.25 (2H, d, J=8Hz, aromatic) and 8.22 (2H, d, J=9.1 Hz, aromatic).

MS (ESI⁺) (m/z): 690 (M+H⁺).

3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-carboxyphenoxy]-3-methyl-2-butanone

A solution of3-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone(0.400 g, 0.58 mmol) in 10 ml of a 1M solution of hydrochloric acid inacetic acid was stirred at 22° C. for 1.5 hours. The solvent wasevaporated in vacuo and the residue was partitioned betweendichloromethane and water while the pH of the aqueous phase was adjustedto 4.5 with 0.1N sodium hydroxide. The organic phase was dried(magnesium sulfate) concentrated and the residue was chromatographed onsilica gel. Elution with a gradient of methanol (0-20%) in ethyl acetategave 0.167 g (45%) of the title material as a syrup. The hydrochloridesalt was prepared and obtained as a foam.

¹H NMR (hydrochloride salt) 400 MHz (DMSO-d₆) δ (ppm): 1.48 (6H, s,2×CH₃), 1.95 (2H, m, CH₂), 2.95 (3H, broad s, NCH₃), 2.98 and 3.1 (2×1H,2m, CH₂), 3.80 and 4.0 (2×1H, 2m, NCH₂), 4.67 (1H, t, J=7.6 Hz, CH),5.44 (2H, s, OCH₂), 6.92 (2H, d, J=8.6 Hz, aromatic), 6.99 (2H, d, J=8.8Hz, aromatic), 7.15 (2H, d, J=8.6 Hz, aromatic), 7.5 (8H, m, aromatic)and 7.88 (2H, d, J=8.8 Hz, aromatic).

HRMS (FAB) calculated for C₃₆H₃₈Cl₂NO₅ [MH]⁺: 634.21271, Found:634.2110, δ 2.7 ppm.

Example 6 (2R and2S)-3-[4-[3-[N-[2-(Bis-[4-chlorophenyl)ethyl]N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-acetoxypropane

(2R and2S)-3-[4-[3-(tert-Butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane

A solution of (2R and2S)-3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanol(6.08 g, 9.5 mmol) in a mixture of pyridine (15 ml) and acetic anhydride(15 ml) was stirred at 22° C. for 1 hour. The excess reagents were thenevaporated in vacuo and the residue was filtered through a silica gelpad (elution toluene-ethyl acetate, 95:5) to give 6.48 g (100%) of thetitle material as a clear oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.08 (9H, s, t-Bu) 1.60 (9H, s, tBu),1.85 (2H, m, CH₂), 2.14 (3H, s, CH₃CO), 2.68 (2H, t, J=7.6 Hz, CH₂),3.69 (2H, t, J=6.3 Hz, OCH₂), 4.24 (2H, d, J=5.1 Hz, OCH₂), 4.33 (2H, d,J=4.5 Hz, OCH₂), 5.52 (1H, m, CH), 6.84 (2H, d, J=8.7 Hz, aromatic),6.94 (2H, d, J=9.0 Hz, aromatic), 7.10 (2H, d, J=8.7 Hz, aromatic), 7.4and 7.68 (6H and 4H, 2m, aromatic) and 7.96 (2H, d, J=9.0 Hz, aromatic).

Anal. Calcd. for C₄₁H₅₀O₇Si: C, 72.11; H, 7.38. Found: C, 72.06; H,7.55.

(2R and2S)-3-[4-(3-Hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane

A solution of (2R and2S)-3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane(7.38 g, 10.8 mmol) in tetrahydrofuran (100 ml) was treated with aceticacid (3.7 ml) and 24 ml (24 mmol) of a 1M solution of tetrabutylammoniumfluoride in tetrahydrofuran and the resulting mixture was heated at 70°C. for 4 hours. The cooled mixture was diluted with ethyl acetate,washed with water, saturated sodium bicarbonate, brine and dried(magnesium sulfate). Evaporation of the solvent and chromatography ofthe residue on silica gel (elution toluene-ethyl acetate, 75:25) gave4.76 g (97%) of the title alcohol as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.60 (9H, s, t-Bu) 1.88 (2H, m, CH₂),2.14 (3H, s, CH₃CO), 2.68 (2H, t, J=7.5 Hz, CH₂), 3.68 (2H, t, J=6.5 Hz,OCH₂), 4.24 (2H, d, J=5.07 Hz, OCH₂), 4.31 (2H, d, J=3.44 Hz, OCH₂),5.51 (1H, M, CH), 6.86 (2H, d, J=8.5 Hz, aromatic), 6.93 (2H, d, J=8.8Hz, aromatic), 7.14 (2H, d, J=8.5 Hz, aromatic) and 7.95 (2H, d, J=8.8Hz, aromatic).

Anal. Calcd. for C₂₅H₃₂O₇: C, 67.01; H, 7.29. Found: C, 66.98; H, 7.34.

(2R and 2S)-3-[4-(3-Methanesulfonyloxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane

A solution of (2R and2S)-3-[4-[3-(hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane(4.71 g, 10.6 mmol) in dichloromethane (70 ml) was cooled to 0° C. andtreated with triethylamine (3.1 ml, 22.2 mmol) followed bymethanesulfonyl chloride (1.4 ml, 18.1 mmol) added dropwise over 5minutes. After 1 hour at 0-5° C., the reaction mixture was quenched byaddition of water and ethyl acetate. The organic phase was washed withwater, saturated sodium bicarbonate and brine and dried (magnesiumsulfate). Evaporation of the solvent and chromatography of the residueon silica gel (elution toluene-ethyl acetate, 9:1) gave 5.44 g (98%) ofthe title material as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 1.60 (9H, s, t-Bu) 2.06 (2H, m, CH₂),2.15 (3H, s, CH₃CO), 2.72 (2H, t, J=7.5 Hz, CH₂), 3.02 (3H, s, OMs),4.23 (2H, t, J=6.0 Hz, OCH₂), 4.25 (2H, d, J=3.6 Hz, OCH₂), 4.31 (2H, d,J=4.36 Hz, OCH₂), 5.51 (1H, m, CH) 6.88 (2H, d, J=8.7 Hz, aromatic),6.94 (2H, d, J=9.0 Hz, aromatic), 7.13 (2H, d, J=8.7 Hz, aromatic) and7.95 (2H, d, J=8.7 Hz, aromatic).

Anal. Calcd. for C₂₆H₃₄O₉S.0.7 H₂O: C, 58.35; H, 6.67. Found: C, 58.35;H, 6.65.

(2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane

A mixture of (2R and2S)-3-[4-(3-methanesulfonyloxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane(5.39 g, 10.3 mmol) and N-methyl-2-bis-(4-dichlorophenyl)ethylamine(3.21 g, 11.4 mmol) in acetonitrile (100 ml) was treated withN,N-diisopropylethylamine (2.3 ml, 13.2 mmol) and sodium iodide (0.1 g)and the resulting mixture was heated at 80° C. for 18 hours. The cooledmixture was diluted with ethyl acetate, washed with water, saturatedsodium bicarbonate and dried (magnesium sulfate). Evaporation of thesolvent and chromatography of the residue on silica gel (elutiontoluene-ethyl acetate, 8:2) gave 5.74 g (79%) of the title material as aclear syrup.

¹H NMR 400 MHz (DMSO-d₆) δ (ppm): 1.53 (9H, s, t-Bu) 1.57 (2H, m, CH₂),2.06 (3H, s, CH₃CO), 2.16 (3H, s, NCH₃), 2.31 (4H, m, 2×CH₂), 2.85 (2H,d, J=8.0 Hz, NCH₂), 4.23 (3H, m, OCH₂ and CH), 4.33 (2H, m, OCH₂), 5.42(1H, m, CH), 6.85 (2H, d, J=8.6 Hz, aromatic), 6.99 (2H, d, J=8.6 Hz,aromatic), 7.06 (2H, d, J=9.1 Hz, aromatic) and 7.85 (2H, d, J=9.1 Hz,aromatic).

Anal. Calcd. for C₄₀H₄₅Cl₂NO₆: C, 67.98; H, 6.42; N, 1.98. Found: C,67.97; H, 6.46; N, 2.05.

(2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-acetoxypropane

A solution of (2R and2S)-3-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane(0.390 g, 0.55 mmol) in 10 ml of 1M hydrochloric acid in acetic acid wasstirred at 22° C. for 1.5 hours. The solvent was then evaporated invacuo and the residue was partitioned between dichloromethane and waterwhile the pH of the aqueous phase was adjusted to 4.5 with 0.1N sodiumhydroxide. The aqueous phase was extracted twice with dichloromethaneand the combined organic phases were dried (magnesium sulfate) andconcentrated. Chromatography of the residue on silica gel (elution ethylacetate-methanol, 0-20%) gave 0.27 g (76%) of the title material as awhite foam. The hydrochloride salt was prepared and obtained as anamorphous solid.

¹H NMR (hydrochloride salt) 400 MHz (DMSO-d₆) δ (ppm): 0.87 (2H, m,CH₂), 2.06 (3H, s, CH₃CO), 2.47 (2H, m, CH₂), 2.72 (3H, broad s, NCH₃),2.92 and 3.03 (2×1H, 2 m, NCH₂), 3.8 and 3.98 (2×1H, 2m, NCH₂), 4.24(2H, m, OCH₂), 4.37 (2H, m, OCH₂), 4.71 (1H, broad t, J=6.7 Hz, CH),5.43 (1H, m, CH), 6.91 (2H, d, J=8.4 Hz, aromatic), 7.06 (2H, d, J=8.5Hz, aromatic), 7.10 (2H, d, J=8.4 Hz, aromatic), 7.43 (8H, m, aromatic)and 7.89 (2H, d, J=8.5 Hz, aromatic).

Anal. Calcd. for C₃₆H₃₇Cl₂NO₆.HCl.2HO: C, 59.80; H, 5.85; N, 1.94.Found: C, 59.68; H, 5.50; N, 1.95.

Example 7 (2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-trimethylacetoxypropane

(2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanol

A solution of (2R and2S)-3-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane(4.19 g, 5.93 mol) in 80% ethanol (100 ml) was treated with a solutionof potassium hydroxide (2 g) in water (5 ml) and the resulting mixturewas heated at 80° C. for 1 hour. The cooled mixture was concentrated invacuo, diluted with ethyl acetate, washed with water and brine and dried(magnesium sulfate). Evaporation of the solvent and chromatography ofthe residue on silica gel (elution toluene-ethyl acetate, 7:3) gave 3.52g (89%) of the title material as a foam.

¹H NMR 400 MHz (DMSO-d₆) δ (ppm): 1.53 (9H, s, t-Bu), 1.58 (2H, m, CH₂),2.16 (3H, s, NCH₃), 2.3 (4H, m, 2×CH₂), 2.85 (2H, d, J=8.1 Hz, NCH₂),3.9-4.2 (5H, m, 2×OCH₂ and CH), 4.23 (1H, t, J=8.1 Hz, CH), 5.4 (d,J=5.5 Hz, OH), 6.84 (2H, d, J=8.6 Hz, aromatic), 6.97 (2H, d, J=8.6 Hz,aromatic), 7.04 (2H, d, J=8.7 Hz, aromatic), 7.32 (8H, s, aromatic) and7.84 (2H, d, J=8.7 Hz, aromatic).

Anal. Calcd. for C₃₈H₄₃Cl₂NO₅.0.5 H₂O: C, 67.75; H, 6.58; N, 2.08.Found: C, 67.87; H, 6.40; N, 2.13.

(2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-tert-butoxycarbonyl)phenoxy]-2-trimethylacetoxypropane

A solution of (2R and2S)-3-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanol(0.593 g, 0.89 mmol) in tetrahydrofuran (10 ml) was treated at 22° C.with pyridine (0.6 ml) and 4-(dimethylamino)pyridine (0.055 g) followedby trimethylacetyl chloride (0.5 ml, 4.1 mmol) added dropwise over 5minutes. After 18 hours at 22° C., the reaction mixture was diluted withethyl acetate, washed with water, saturated sodium bicarbonate, brineand dried (magnesium sulfate). Evaporation of the solvent andchromatography of the residue on silica gel (elution toluene-ethylacetate, 9:1) gave 0.485 g (73%) of the title material as an oil.

¹H NMR 400 MHz (DMSO-d₆) δ (ppm): 1.1 (9H, s, t-Bu), 1.53 (9H, s, t-Bu),1.59 (2H, m, CH₂), 2.16 (3H, s, NCH₃), 2.3 (4H, m, 2×CH₂), 2.85 (2H, d,J=8.2 Hz, NCH₂), 4.2-4.4 (5H, m, 2×OCH₂ and CH), 5.41 (1H, m, CH), 6.85(2H, d, J=8.6 Hz, aromatic), 6.98 (2H, d, J=8.6 Hz, aromatic), 7.05 (2H,d, J=9.1 Hz, aromatic), 7.32 (8H, s, aromatic) and 7.85 (2H, d, J=9.1Hz, aromatic).

Anal. Calcd. for C₄₃H₅₁Cl₂NO₆: C, 68.97; H, 6.87; N, 1.87. Found: C,68.70; H, 7.01; N, 1.89.

(2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-trimethylacetoxypropane

A solution of (2R and2S)-3-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-trimethylacetoxypropane(0.450 g, 0.60 mmol) in 10 ml of 1M hydrochloric acid in acetic acid wasstirred at 22° C. for 1 hour. The solvent was then evaporated in vacuoand the residue was partitioned between dichloromethane and water whilethe pH of the aqueous phase was adjusted to 4.5 with 0.1N sodiumhydroxide. The organic phase was dried (magnesium sulfate), evaporatedand the residue was chromatographed on silica gel (elution ethylacetate-methanol; 8:2) to give 0.326 g (78%) of the title material as awhite foam. The hydrochloride salt was prepared as usual and obtained asa foam.

¹H NMR (hydrochloride salt) 400 MHz (DMSO-d₆) δ (ppm): 1.1 (9H, s,t-Bu), 1.9 (2H, m, CH₂), 2.48 (2H, m, CH₂), 2.74 (3H, broad s, NCH₃),3.0 (2H, m, NCH₂), 3.79 and 3.98 (2×1H, 2m, NCH₂), 4.25 (2H, AB part ofABX system, J_(AB)=11.0 Hz, J_(AX)=6.2 Hz, J_(BX)=4.1 Hz, OCH₂), 4.35(2H, AB part of ABX system, J_(AB)=11.0 Hz, J_(AX)=6.1 Hz, J_(BX)=4.1Hz, OCH₂), 4.67 (1H, broad t, J=7.3 Hz, CH), 5.42 (1H, m, CH), 6.91 (2H,d, J=8.1 Hz, aromatic), 7.06 (2H, d, J=9.1 Hz, aromatic), 7.1 (2H, d,J=8.1 Hz, aromatic) and 7.9 Hz (2H, d, J=9.1 Hz, aromatic).

Anal. Calcd. for C₃₉H₄₃Cl₂NO₆.HCl.2.5 H₂O: C, 60.51; H, 6.38; N, 1.81.Found: C, 60.53; H, 5.82; N, 1.84.

Example 8 (2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-propylamine

(2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-(tert-butoxycarbonyl)phenoxy]-2-azidopropane

A solution of3-[4-[3-[N-[2-bis-(chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-[4-(tert-butoxycarbonyl)phenoxy]-2-propanol(2.61 g, 3.93 mmol) and triphenylphosphine (1.65 g, 6.3 mol) intetrahydrofuran (60 ml) at 0-5° C. was treated with 17 ml (11.9 mmol) ofa 0.7 solution of hydrazoic acid in toluene. Then a solution of diethylazodicarboxylate (1.06 ml, 6.7 mmol) in tetrahydrofuran (5 ml) was addeddropwise over 10 minutes. After 3 hours at 0-5° C., the reaction mixturewas diluted with ethyl acetate, washed with saturated sodiumbicarbonate, brine and dried (magnesium sulfate). Evaporation of thesolvent and chromatography of the residue on silica gel (elutiontoluene-ethyl acetate, 9:1) gave 2.08 g (77%) of the title material asan oil.

¹H NMR 400 MHz (DMSO-d₆) δ (ppm): 1.53 (9H, s, t-Bu) 1.58 (2H, m, CH₂),2.16 (3H, s, NCH₃), 2.32 (4H, m, 2×CH₂), 2.85 (2H, d, J=7.7 Hz NCH₂),4.1-4.4 (6H, m, 2×OCH₂ and 2×CH), 6.87 (2H, d, J=8.6 Hz, aromatic), 7.01(2H, d, J=8.6 Hz, aromatic), 7.07 (2H, d, J=8.8 Hz, aromatic), 7.33 (8H,s, aromatic) and 7.87 (2H, d, J=8.6 Hz, aromatic).

Anal. Calcd. for C₃₈H₄₂Cl₂N₄O₄.0.3 H₂O: C, 65.66; H, 6.18; N, 8.06.Found: C, 65.69; H, 6.28; N, 8.12.

(2R and3S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-(carboxyphenoxy)-2-propylamine

A solution of (2R and2S)-3-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-azidopropane(0.530 g, 0.77 mmol) in a mixture of tetrahydrofuran (25 ml) and water(5 ml) was treated with triphenylphosphine (0.60 g) and the resultingmixture was stirred at 22° C. for 18 hours. The reaction mixture wasthen diluted with ethyl acetate, washed with water, brine and dried(magnesium sulfate). Evaporation of the solvent gave the crude aminethat was then diluted in dichloromethane (20 ml) and treated at 22° C.with trifluoroacetic acid (3 ml). After 3 hours, the solvent wasevaporated in vacuo and the residue was partitioned between ethylacetate and water while the pH of the aqueous phase was adjusted to pH 7with 0.1N sodium hydroxide. The organic phase was dried (magnesiumsulfate), concentrated and the residue was chromatographed on silicagel. Elution with a mixture of ethyl acetate, methanol and water(60:40:2) gave 0.087 g (19%) of the title material as a foam. Thehydrochloride salt was prepared as usual and obtained as an amorphoussolid.

¹H NMR (bis hydrochloride salt) 400 MHz (DMSO-d₆) δ (ppm): 1.9 (2H, m,CH₂), 2.74 (3H, broad s, NCH₃), 3.0 (2H, m, CH₂), 3.79 and 3.98 (1H and2H, 2m, NCH₂ and CH), 4.27 (2H, AB part of ABX system, J_(AB)=10.3 Hz,J_(AX)=5.9 Hz, J_(BX)=3.9 Hz, OCH₂), 4.37 (2H, AB part of ABX system,J_(AB)=10.7 Hz, J_(AX)=6.1 Hz, J_(BX)=4.4 Hz, OCH₂), 4.68 (1H, broad t,J=7.0 Hz, CH), 6.95 (2H, d, J=8.6 Hz, aromatic), 7.10 (2H, d, J=8.8 Hz,aromatic), 7.14 (2H, d, J=8.6 Hz, aromatic), 7.45 (8H, m, aromatic) and7.94 (2H, d, J=8.8 Hz, aromatic).

HRMS (FAB) Calcd. for C₃₄H₃₇O₄N₂ ³⁵Cl₂ [MH]⁺: 607.21301, Found:607.21430, δ 2.1 ppm.

Example 94-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-methoxy-2-butanone

Ethyl 2,2-difluoro-3-iodo-3-(4-methoxyphenyl)propionate

A solution of ethyl 2,2-difluoro-3-hydroxy-3-(4-methoxyphenyl)propionate (5.03 g, 22.4 mmol) [J. M. Andres, et al., Synthesis, (1996)1070-1071] and triethylamine (6.56 ml, 47.0 mmol) in dichloromethane (45ml) was treated at 0° C. with methanesulfonyl chloride (4.36 g, 38.0mmol) added dropwise over 5 minutes. After 30 minutes at 22° C., thereaction mixture was diluted with dichloromethane, washed with 0.1N HCl,brine and dried (magnesium sulfate). Evaporation of the solvent gave anoil (7.92 g) that was diluted with acetone and treated with sodiumiodide (7.22 g). The resulting mixture was then heated at 50° C. for 18hours. The solvent was then concentrated in vacuo and the residue waspartitioned between toluene and water. The organic phase was washed with10% sodium thiosulfate, brine and dried (magnesium sulfate). Evaporationof the solvent and chromatography of the residue on silica gel (elutiontoluene-hexane, 7:3) gave 6.37 g (77%) of the title material as a lightyellow solid: mp 44-45° C.

Anal. Calcd. for C₁₂H₁₃F₂IO₃: C, 38.94; H, 3.54. Found: C, 39.12; H,3.42.

Ethyl 2,2-difluoro-3-(4-methoxyphenyl)-propionate

A solution of ethyl 2,2-difluoro-3-iodo-3-(4-methoxyphenyl)-propionate(5.24 g, 14.2 mmol) in toluene (125 ml) was treated with tributyltinhydride (28.9 g, 0.10 mol) and a few crystals of2,2′-azobisisobutyronitrile. The resulting solution was then irradiatedfor 15 minutes at 25° C. with a sun lamp. The solvent was thenevaporated in vacuo and the residue was partitioned between acetonitrileand pentane. The acetonitrile fraction was concentrated andchromatographed on silica gel (elution hexane-ethyl acetate, 85:15) togive 2.65 g (76%) of the title material as an oil: bp 90-95° C./0.1 torr(air bath temperature).

Anal. Calcd. for C₁₂H₁₄F₂O₃: C, 59.01; H, 5.78. Found: C, 58.89; H,5.51.

Ethyl 2,2-difluoro-3-phenoxythiocarboxyloxy-3-(4-methoxyphenyl)propionate

A solution of ethyl 2,2-difluoro-3-hydroxy-3-(4-methoxyphenyl)propionate(3.01 g, 11.6 mmol) in dichloromethane (30 ml) was cooled to 0° C., andreacted with pyridine (4.5 g, 56.0 mmol) followed byphenylchlorothionoformate (2.49 g, 14.4 mmol) added dropwise over 5minutes. The resulting mixture was then stirred at 22° C. for 18 hours.The reaction mixture was then quenched by addition of water anddichloromethane. The organic phase was washed with water, 1Nhydrochloric acid, saturated sodium bicarbonate and brine. After drying,the solvent was evaporated in vacuo and the residue was chromatographedon silica gel. Elution with a mixture of hexane and toluene (1:1) gave4.58 g (100%) of the title material as a clear oil.

Anal. Calcd. for C₁₉H₁₈F₂O₅S: C, 57.57; H, 4.58. Found: C, 57.59; H,4.70.

Ethyl 2,2-difluoro-3-(4-methoxyphenyl)-propionate

A solution of ethyl2,2-difluoro-3-phenoxythiocarbonyloxy-3-(4-methoxyphenyl) propionate(5.10 g, 12.9 mmol) in benzene (80 ml) was treated with tributyltinhydride (4.5 g, 15.5 mmol) and 2,2′-azobiisobutyronitrile (AIBN, 0.070g) and the resulting mixture was heated under reflux for 3 hours. Thesolvent was evaporated under reduced pressure and the residue waschromatographed on silica gel (elution toluene-hexane 1:1) to give 2.52g (80%) of the title material as an oil: bp 90-95° C./0.1 torr (air bathtemperature).

Ethyl 2,2-difluoro-3-(4-hydroxyphenyl)-propionate

A solution of ethyl 2,2-difluoro-3-(4-hydroxyphenyl)-propionate (2.0 g,8.18 mmol) in dichloromethane (80 ml) was reacted dropwise at 0° C. with37 ml (37 mmol) of a 1M solution of boron tribromide in dichloromethane.After 2.5 hours at 0° C., the mixture was quenched by the addition ofice water and dichloromethane. The organic phase was washed with water,dried over anhydrous sodium sulfate and evaporated in vacuo.Chromatography of the residue on silica gel (elution hexane-ethylacetate, 7:3) gave 1.50 g (80%) of the title material as an oil.

Anal. Calcd. for C₁₁H₁₂F₂O₃: C, 57.39; H, 5.25. Found: C, 57.06; H,5.44.

3-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoropropanoicacid methyl ester

In A solution of ethyl 2,2difluoro-3-(4-hydroxyphenyl)-propionate (1.0g, 4.34 mmol), 2-[N-[2-bis-(chlorophenyl)ethyl]-N-methylamino]ethanol(1.52 g, 4.68 mmol) and triphenylphosphine (1.25 g, 4.76 mmol) inbenzene (20 ml) was treated at 22° C. with diethyl azodicarboxylate(0.831 g, 4.77 mmol) added dropwise over 2 minutes. After 2.5 hours at22° C., the resulting mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate, brine and dried over anhydrousmagnesium sulfate. Evaporation of the solvent and chromatography of theresidue on silica gel (elution toluene-ethyl acetate, 92:8) gave 1.32 g(57%) of the title material as an oil.

Anal. Calcd. for C₂₈H₂₉Cl₂F₂NO₃: C, 62.69; H, 5.45; N, 2.61. Found: C,62.83; H, 5.58; N, 2.62.

3-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoropropanoicacid

A solution of3-[4-[2-[N-[2-bis-(chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoropropanoicacid methyl ester (1.15 g, 2.14 mmol) in a mixture of ethanol (9 ml) andwater (3 ml) was treated with potassium hydroxide (0.28 g, 5.0 mmol) andthe resulting mixture was stirred at 22° C. for 4 hours. The mixture wasthen cooled to 0° C. and adjusted to pH 3.0 with 1N hydrochloric acidand concentrated in vacuo. The residue was extracted twice withdichloromethane and the combined organic phases were washed with brineand dried (magnesium sulfate). Evaporation of the solvent andrecrystallization of the solid residue from ethyl acetate-hexane gave1.09 g (quantitative) of the title material as a white solid: mp 74-78°C.

Anal. Calcd. for C₂₆H₂₅Cl₂F₂NO₃: C, 61.43; H, 4.96; N, 2.76. Found: C,61.02; H, 5.63; N, 2.49.

N-Methoxy-N-methyl3-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoropropionamide

A solution of3-[4-[2-[N-2-bis(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2difluoropropanoicacid (1.09 g, 2.0 mmol) in dichloromethane (10 ml) was cooled to −25° C.and treated with N-methylmorpholine (0.25 g, 2.46 mmol) followed byisobutyl chloroformate (0.33 g, 2.4 mmol). After 5 min, the mixture wastreated with a suspension of N,O-dimethylhydroxylamine hydrochloride(0.26 g, 2.7 mmol) and N-methylmorpholine (0.28 g, 2.7 mmol) indichloromethane (9 ml). The resulting mixture was allowed to warm up to22° C. and stirred for 2.5 hours. The reaction was then quenched byaddition of saturated aqueous sodium bicarbonate and dichloromethane.The organic phase was washed with brine, dried (magnesium sulfate) andevaporated. Chromatography of the residue on silica gel (elutionhexane-ethyl acetate, 6:4) gave 0.95 g (86%) of the title material as anoil.

Anal. Calcd. for C₂₈H₃₀Cl₂F₂N₂O₃: C, 60.99; H, 5.48; N, 5.08. Found: C,61.0; H, 5.59; N, 5.13.

4-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-methoxy-2-butanone

A solution of methoxymethyltributyltin (0.296 g, 0.88 mmol) intetrahydrofuran (2 ml) at −78° C. was treated with n-butyllithium (0.40ml of a 2.08 M solution in hexane, 0.83 mmol). After 10 min, a solutionof N-methoxy-N-methyl3-[4-[2-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoropropiona-mide(0.199 g, 0.36 mmol) in tetrahydrofuran (1 ml) was added and theresulting mixture was stirred at −78° C. for 15 minutes. The temperatureof the reaction mixture was then allowed to reach 22° C. over 20 minutesand the reaction was quenched by the addition of saturated aqueoussodium bicarbonate and dichloromethane. The organic phase was washedwith brine, dried (magnesium sulfate) and evaporated. Chromatography ofthe residue on silica gel (elution toluene-tetrahydrofuran, 85:15) gave0.150 g (80%) of the title material as oil. The hydrochloride salt wasobtained as a white solid: mp 53-62° C.

Anal. Calcd. for C₂₈H₂₉Cl₂F₂NO₃.HCl.0.4 H₂O: C, 57.97; H, 5.35, N 2.41.Found: C, 58.10; H, 5.67; N, 2.55.

Example 104-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-[4-(4,5-dihydro-2-oxazolyl)phenoxy]-2-butanone

2-[4-(Tributylstannylmethoxy)phenyl]-4,6-dihydrooxazole

A solution of 4-(4,5-dihydro-2-oxazolyl)phenol (0.145 g, 0.89 mmol) (G.D. Diana, et al., J. Med. Chem., 1985, 28, 1906-1910) andiodomethyltributyltin (0.52 g, 1.2 mmol) (D. E. Seitz, et al., SyntheticCommun., 1983, 13, 129-134) in N,N-dimethylformamide (3 ml) was treatedwith powdered potassium carbonate (0.31 g, 2.2 mmol) and the resultingmixture was heated at 70° C. for 15 hours. The reaction mixture was thendiluted with ethyl acetate-hexane (6:4) washed with water, brine anddried (magnesium sulfate). Evaporation of the solvent and chromatographyof the residue on silica gel (elution toluene-ethyl acetate, 8:2) gave0.360 g (86%) of the title material as an oil.

4-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-[4-(4,5-dihydro-2-oxazolyl)phenoxy]-2-butanone

A solution of 2-[4-(tributylstannylmethoxy)phenyl]-4,5-dihydrooxazole(0.330 g, 0.71 mmol) in tetrahydrofuran (2 ml) at −78° C. was treatedwith 0.33 ml (0.68 ml) of a 2.08 M solution of butyllithium in hexane.After 10 min, a solution of N-methoxy-N-methyl3-[4-[2-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoropropionamide(0.170 g, 0.31 mmol) in tetrahydrofuran (1 ml) was added and resultingmixture was stirred at −78° C. for 15 minutes. The temperature of themixture was then warmed to 20° C. over 20 minutes and the reaction wasquenched by addition of saturated aqueous sodium bicarbonate and ethylacetate. The organic phase was washed with brine, dried (magnesiumsulfate) and evaporated. Chromatography of the residue on silica gel(elution ethyl acetate-methanol 0-2%) gave 0.107 g (52%) of the titlematerial as a white glassy solid.

HRMS (ESI⁺) (M+H)⁺ calcd: 667.19418 Found: 667.1948, δ=−0.9 ppm.

Example 114-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenoxy]-2-butanone

Reaction of N-methoxy-N-methyl3-[4-[2-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoropropionamide(0.20 g, 0.36 mmol) with2-[4-(tributylstannylmethoxy)phenyl]-4,4-dimethyl-4,5-dihydrooxazole(0.391 g, 0.79 mmol) using the conditions described in Example 9 gave0.108 g (43%) of the title material as a syrup.

MS (ESI⁺) (m/z): 695 (M+H)⁺.

Example 12[4-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-[4-(2-aminocarboxyethyl)phenoxy]-2-butanone,dihydrochloride salt

A solution of4-[4-[2-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-[4-(4,5-dihydro-2-oxazolyl)phenoxy]-2-butanone(0.071 g, 0.4 mmol) in a mixture of tetrahydrofuran (3 ml) and 1Naqueous hydrochloric acid (0.7 ml) was heated in a sealed tube at 100°C. for 15 minutes. The solvent was then evaporated in vacuo and theresidue was extracted with boiling acetonitrile. Evaporation of theacetonitrile extract gave 0.060 g (72%) of the title material as aglassy solid.

MS (ESI⁺) (m/z): 685, (M+H)⁺.

Example 134-[4-[2-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-(4-carboxyphenoxy)-2-butanone

A solution of4-[4-[2-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]ethoxy]phenyl]-2,2-difluoro-1-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenoxy]-2-butanone(0.075 g, 0.11 mmol) in dioxane (1.5 ml) was treated with 2.0 ml of 4.8Naqueous hydrochloric acid and the resulting mixture was heated at 100°C. in a sealed tube for 6 hours. The cooled mixture was concentrated invacuo and the residue was dissolved in a small amount of tetrahydrofuranand water. After adjusting to pH 4, the mixture was diluted withdichloromethane and washed with water. The organic phase was dried,concentrated in vacuo and chromatographed on silica gel plates (elutiondichloromethane-methanol, 9:1) to give 0.015 g (20%) of the titlematerial as an amorphous solid. The hydrochloride salt was prepared andobtained as a white solid.

MS (ESI⁺) (m/z) 642 (M+H)⁺.

Example 14 (2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-(2-oxopropionamido)propane

(2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-(2-oxopropionamido)propane

A solution of (2R and2S)-3-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methyl-amino]propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-azidopropane(3.04 g, 4.4 mmol) in a mixture of tetrahydrofuran and water was reducedas described in Example 8 with triphenylphosphine (3.4 g, 13.1 mmol).The crude product obtained after work-up was diluted withdichloromethane (30 ml) cooled to 0° C. and treated with pyridine (0.3ml) followed by 2-oxopropionyl chloride (0.5 g, 4.6 mmol). After 30minutes at 0-5° C., the reaction mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate, brine and dried (magnesiumsulfate). Evaporation of the solvent and chromatography of the residueon silica gel (elution toluene-ethyl acetate, 75:25) gave 0.191 g (6%)of the title material as an oil.

¹H NMR 400 MHz (DMSO-d₆) δ (ppm): 1.53 (9H, s, tBu), 1.57 (2H, m, CH₂),2.16 (3H, s, NCH₃), 2.31 (4H, m, 2×CH₂), 2.37 (3H, s, COCH₃), 2.85 (2H,d, J=8.1 Hz, NCH₂), 4.1-4.3 (5H, m, 2×OCH₂ and CH), 4.47 (1H, m, CH),6.84 (2H, d, J=8.6 Hz, aromatic), 6.98 (2H, d, J=8.6 Hz, aromatic), 7.03(2H, d, J=9.0 Hz, aromatic), 7.33 (8H, s, aromatic), 7.84 (2H, d, J=9.0Hz, aromatic), 8.84 (1H, d, J=8.5 Hz, NH).

MS (ESI⁺) (m/z): 733 (M+H)⁺

(2R and2S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-carboxyphenoxy)-2-(2-oxopropionamido)propane

A solution of (2R and2S)-3-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-1-(4-(tert-butoxycarbonyl)phenoxy])-2-(2-oxopropionamido)propane(0.158 g, 0.21 mmol) in dichloromethane (10 ml) was treated at 22° C.with trifluoroacetic acid (1.5 ml) and the resulting mixture was stirredfor 2.5 hours. The solvent and the excess reagent were then evaporatedin vacuo. The residue was diluted with dichloromethane, washed with pH 6phosphate buffer, dried (magnesium sulfate) and concentrated.Chromatography of the residue on silica gel (elution toluene-ethylacetate, 1:1) gave 0.099 g (68%) of the title material as a syrup. Thehydrochloride salt was prepared as usual and obtained as an amorphoussolid.

¹H NMR (free amine) 400 MHz (DMSO-d₆) δ (ppm): 1.57 (2H, m, CH₂), 2.16(3H, s, NCH₃), 2.30 (4H, m, 2×CH₂), 2.37 (3H, s, COCH₃), 2.85 (2H, d,J=8.2 Hz, NCH₂), 4.1-4.3 (5H, m, 2×OCH₂ and CH), 4.47 (1H, m, CH), 6.84(2H, d, J=8.5 Hz, aromatic), 6.99 (4H, m, aromatic), 7.33 (8H, s,aromatic), 7.87 (2H, d, J=9.1 Hz, aromatic), 8.91 (1H, d, J=8.7 Hz, NH).

HRMS (ESI⁺) Calcd. for C₃₇H₃₉N₂O₆ ³⁵Cl₂ [MH]⁺: 677.21851 Found:677.21840, δ=0.2 ppm.

Example 15 (3R and3S)-3-[4-[3-[N-[2-Bis-4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-3-methoxy-1-(4-carboxyphenoxy)-2-propanone

Methyl (2R and2S)-2-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-2-methoxyacetate

A solution of4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]N-methylamino]propyl]phenol (2.41g, 5.8 mmol) in ether (25 ml) was treated with triethylamine (1.1 ml,7.9 mmol) followed by chloromethoxyacetic acid methyl ester (1.0 g, 7.3mmol) [H. Grosz and J. Freiberg, Chem. Ber. (1996) 99, 3260] and theresulting mixture was heated under reflux for 16 hours. The solid formedwas filtered and washed with ether. The filtrate was washed withsaturated sodium bicarbonate, dried (magnesium sulfate) and evaporated.Chromatography of the residue on silica gel (elution hexane-ethylacetate, 8:3) gave 3.0 g (100%) of the title material as a clear oil.

¹H NMR 400 MHz (C₆D₆) δ (ppm): 1.63 (2H, m, CH₂), 2.09 (3H, s, NCH₃),2.26 (2H, t, J=6.8 Hz, CH₂), 2.42 (2H, t, J=7.6 Hz, CH₂), 2.66 (2H, d,J=8.0 Hz, NCH₂), 3.39 (6H, s, 2×OCH₃), 3.90 (1H, t, J=8.0 Hz, CH), 5.55(1H, s, CH), 6.88 (4H, d, J=8.7 Hz, aromatic), 6.98 (2H, d, J=8.7 Hz,aromatic), 7.23 (6H, m, aromatic).

Anal. Calcd. for C₂₈H₃₁Cl₂NO₄: C, 65.12; H, 6.05; N, 2.71. Found: C,65.14; H, 6.17; N, 2.79.

(2R and2S)-2-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-2-methoxyaceticacid, hydrochloride salt

A solution of methyl (2R and2S)-2-[4-[3-[N-[3-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-2-methoxyacetate(1.0 g, 1.94 mmol) in 80% aqueous ethanol (20 ml) was treated withpotassium hydroxide (0.15 g) in water (1 ml) and the resulting mixturewas stirred at 25° C. for 1.5 hour. The reaction mixture was thenpartitioned between water and ethyl acetate and the pH of the aqueousphase was adjusted to 3.0. The organic phase was then washed with brine,dried (magnesium sulfate) and concentrated to give 0.86 g (82%) of thetitle salt as a white amorphous solid.

¹H NMR 400 MHz (CD₃OD) δ (ppm): 2.0 (2H, m, CH₂), 2.64 (2H, t, J=7.4 Hz,CH₂), 2.90 (3H, s, NCH₃), 3.17 (2H, broad t, CH₂), 3.48 (3H, s, OCH₃),3.9 (2H, broad d, CH₂), 4.49 (1H, t, J=8.1 Hz, CH), 5.48 (1H, s, CH),7.07 (2H, d, J=8.6 Hz, aromatic), 7.17 (2H, d, J=8.6 Hz, aromatic), 7.4(8H, m, aromatic).

Anal. Calcd. for C₂₇H₂₉Cl₂NO₄.HCl: C, 60.18, H5.61; N, 2.60. Found: C,59.69; H, 5.49; N, 2.64.

(2R and2S)-2-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-2-methoxy-N-methoxy-N-methylacetamide

A solution of (2R and2S)-2-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-2-methoxyaceticacid, hydrochloride salt (0.80 g, 1.48 mmol) in dichloromethane (15 ml)was treated with oxalyl chloride (0.25 ml, 2.9 mmol) and a trace ofN,N-dimethylformamide and the resulting mixture was stirred at 22° C.for 2.5 hours. The solvent and excess reagents were evaporated in vacuoand the residue was diluted with dichloromethane (15 ml) and cooled to0-50° C. Then N,O-dimethylhydroxylamine hydrochloride (0.18 g, 1.8 mmol)followed by pyridine (0.4 ml) were added and the resulting mixture wasstirred at 22° C. for 30 minutes. The reaction mixture was then dilutedwith ethyl acetate, washed with sodium bicarbonate, brine and dried(magnesium sulfate). Evaporation of the solvent and chromatography ofthe residue on silica gel (elution hexane-ethyl acetate, 1:1) gave 0.30g (37%) of the title amide as an oil.

¹H NMR 400 MHz (C₆D₆) δ (ppm): 1.64 (2H, m, CH₂), 2.10 (3H, s, NCH₃),2.28 (2H, t, J=6.9 Hz, CH₂), 2.44 (2H, t, J=7.7 Hz, CH₂), 2.67 (2H, d,J=8.2 Hz, NCH₂), 2.9 (3H, broad s, NCH₃), 3.25 and 3.59 (2×3H, 2 broads, 2×OCH₃), 3.25 and 3.59 (2×3H, 2 broad s, 2×OCH₃), 3.9 (1H, t, J=8.2Hz, CH), 6.12 (1H, broad s, CH), 6.89 (4H, d, J=8.3 Hz, aromatic), 7.03(2H, d, J=8.7 Hz, aromatic), 7.24 (4H, d, J=8.3 Hz, aromatic) 7.3 (2H,overlapping with C₆H₆, aromatic).

HRMS (ESI⁺) calcd for C₂₉H₃₅N₂O₄ ³⁵Cl₂ [MH]⁺: 545.19738 Found:545.19792, δ−1.0 ppm

1,1-Dimethylethyl 4-(tributylstannylmethoxy)benzoate

A solution of 1,1-dimethylethyl 4-hydroxybenzoate (0.20 g, 1.04 mmol) inN,N-dimethylformamide (4 ml) was treated with powdered anhydrouspotassium carbonate (0.4 g) followed by iodomethyltributyltin (0.60 g,1.4 mmol) [D. E. Seitz, et al, Synth. Commun. (1983) 13, 129-134] andthe resulting mixture was stirred at 65° C. for 1 hour. The cooledreaction mixture was diluted with a mixture of hexane and ethyl acetate(9:1), washed with water, brine and dried (magnesium sulfate).Evaporation of the solvent and chromotography of the residue on silicagel (elution hexane-toluene, 1:1) gave 0.494 g (96%) of the titlematerial as an oil.

¹H NMR 400 MHz (CDCl₃) δ (ppm): 0.9 (9H, t, J=7.3 Hz, 3×CH₃), 0.98 (6H,broad t, CH₂), 1.32 (6H, m, 3×CH₂), 1.53 (6H, m, 3×CH₂), 1.59 (9H, s,t-Bu), 4.21 (2H, s, OCH₂), 6.93 (2H, d, J=8.8 Hz, aromatic), 7.93 (2H,d, J=8.8 Hz, aromatic).

(3R and3S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-3-methoxy-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone

A solution of 1,1-dimethylethyl 4-(tri-butylstannylmethoxy)benzoate(0.29 g, 0.58 mmol) in dry tetrahydrofuran (5 ml) was cooled to −100° C.and treated with 0.36 ml of 1.6M butyllithium (0.58 mmol) in hexane.After 10 minutes at −100° C., a solution of (2R and2S)-2-[4-[3-[N-[2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-2-methoxy-N-methoxy-N-methylacetamide(0.30 g, 0.55 mmol) in tetrahydrofuran (5 ml) was added dropwise over 5minutes. After 10 minutes at −100° C., the temperature of the reactionmixture was allowed to warm up to 22° C. over 1 hour. The reactionmixture was then quenched by addition of saturated sodium bicarbonateand ethyl acetate. The organic phase was washed with brine, dried(magnesium sulfate) and concentrated. Chromatography of the residue onsilica gel (elution hexane-ethyl acetate, 7:3) gave 0.147 g (39%) of thetitle material as an oil.

¹H NMR 400 MHz (C₆D₆) δ (ppm): 1.58 (9H, s, t-Bu), 1.64 (2H, m. CH₂),2.12 (3H, s, NCH₃), 2.29 (2H, t, J=6.8 Hz, CH₂), 2.44 (2H, t, J=7.6 Hz,CH₂), 2.69 (2H, d, J=8.0 Hz, NCH₂), 3.18 (3H, s, OCH₃), 3.92 (1H, t,J=8.0 Hz, CH), 4.83 (2H, AB system, J_(AB)=18.3 Hz, Δνv=21.6 Hz, OCH₂),5.16 (1H, s, CH), 6.81 (2H, d, J=8.8 Hz, aromatic), 6.90 (4H, d, J=8.5Hz, aromatic), 6.97 (2H, d, J=8.6 Hz, aromatic), 7.07 (2H, d, J=8.6 Hz,aromatic), 7.24 (4H, d, J=8.5 Hz, aromatic), 8.18 (2H, d, J=8.8 Hz,aromatic).

HRMS (ESI⁺) calcd for C₃₉H₄NO₆ ³⁵Cl₂ [MH]⁺: 692.25458 Found: 692.25310,δ 2.1 ppm

(3R and3S)-3-[4-[3-[N-[2-Bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-3-methoxy-1-[4-carboxyphenoxy)-2-propanone,trifluoroacetic salt

A solution of (3R and3S)-3-[4-[3-[N-2-bis-(4-chlorophenyl)ethyl]-N-methylamino]propyl]phenoxy]-3-methoxy-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone(0.105 g, 0.15 mmol) in dichloromethane (5 ml) was treated at 22° C.with trifluoroacetic acid (1 ml). After 1 hour, the solvent and excessreagent were evaporated in vacuo. The residue was dissolved in a mixtureof water and acetonitrile and lyophilized to give 0.113 g (quantitative)of the title trifluoroacetate salt as a white amorphous solid.

¹H NMR 400 MHz (DMSO-d₆) δ (ppm): 1.8-2.05 (2H, m, CH₂), 2.79 and 2.80(3H, 2s, NCH₃), 2.95-3.2 (2H, m CH₂), 3.46 (3H, s, OCH₃), 3.75 (2H, m,NCH₂), 4.03 (2H, m, NCH₂), 4.61 (1H, broad t, J=7.5 Hz, CH), 5.28 (2H,ABq, J_(AB)=18.7 Hz, Δν=9.32 Hz, OCH₂), 5.76 (1H, s, CH), 6.98 (2H, d,J=8.9 Hz, aromatic), 7.07 (2H, d, J=8.6 Hz, aromatic) 7.18 (2H, d, J=8.6Hz, aromatic), 7.5 (8H, m, aromatic), 7.87 (2H, d, J=8.9 Hz, aromatic).

HRMS (ESI⁻) calcd for C₃₅H₃₄O₆N³⁵Cl₂ [M−H]⁻: 634.17633 Found: 634.17940,δ 4.8 ppm

TABLE A EXAMPLE STRUCTURE ANALYSIS 16

C₃₄H₃₅Cl₂NO₅.HCl MS (ESI⁺) (m/z): m/e 608 (M + H)⁺ 17

C₂₉H₃₆O₄Si.0.2 H₂O Calcd: C 72.52, H 7.64 Found: C 72.51, H 7.52 18

C₂₈H₃₁Cl₂NO₃.HCl. 0.7 H₂O C 61.20 H 6.13, N 2.55 Found: C 61.22, H 6.05,N 2.58 19

C₃₅H₄₀O₆Si Calcd: C 71.89, H 6.89 Found: C 71.85, H 6.90 20

C₃₅H₃₈O₆Si Calcd: C 72.14, H 6.57 Found: C 72.07, H 6.65 21

C₃₄H₃₃Cl₂NO₅.HCl. 1.8 H₂O Calcd: C 60.46, H 5.61, N 2.07 Found: C 60.49,H 5.19, N 2.00 22

C₃₄H₃₄Cl₂N₄O₄ MS (ESI⁺) (m/z): 633 (MH⁺) 23

C₃₆H₃₇Cl₂NO₅ HRMS (ESI⁻) calculated for C₃₆H₃₆O₅N³⁵Cl₂ [M − H]⁻:632.1971, found: 632.1994, δ-3.7 ppm 24

C₃₄H₃₅Cl₂NO₅ HRMS (ESI⁺) calculated for C₃₄H₃₆NO₅ ³⁵Cl₂ [M + H]⁺:608.19705, found: 608.19705, δ 0.0 ppm 25

C₃₅H₃₅Cl₂NO₆ MS (ESI⁺) (m/z): 636 [M + H]⁺ 26

C₃₃H₃₁Cl₂NO₄ HRMS (ESI⁻) calculated for C₃₃H₃₀O₄N³⁵Cl₂ [M − H]⁻:574.1552, found: 574.1574, δ-3.8 ppm 27

C₃₆H₃₇Cl₂NO₆ HRMS (ESI⁺) calculated for C₃₆H₃₈ ³⁵Cl₂NO₆ [M + H]⁺:650.207619, found: 650.20832, δ-1.1 ppm 28

C₃₄H₃₃Cl₂NO₆S HRMS (ESI⁺) calculated for C₃₄H₃₄ ³⁵Cl₂NO₆S [M + H]⁺:654.14838, found: 654.1499, δ-2.3 ppm 29

C₃₄H₃₃Cl₂NO₄S MS (ESI⁺) (m/z): 622 [M + H]⁺ 30

C₃₄H₃₃Cl₂F₂NO₄ HRMS (ESI⁺) calculated for C₃₄H₃₄ ³⁵Cl₂F₂NO₄ [M + H]⁺:628.18329, found: 628.1839, δ -1.0 ppm 31

C₃₆H₃₈Cl₂N₂O₅ HRMS (ESI⁺) calculated for C₃₆H₃₉ ³⁵Cl₂N₂O₅ [M + H]⁺:649.22360, found: 649.22376, δ -0.2 ppm 32

C₃₆H₃₆Cl₂N₂O₄ MS (ESI⁺) (m/z): 631 [M + H]⁺ 33

C₃₅H₃₄Cl₂N₂O₆ MS (ESI⁺) (m/z): 649 [M + H]⁺ 34

C₃₅H₃₃Cl₂F₂NO₄ MS (ESI⁺) (m/z): 640 [M + H]⁺ 35

C₃₃H₃₁Cl₂NO₅S MS (ESI⁺) (m/z): 624 [M + H]⁺ 36

C₂₆H₂₅Cl₂F₂NO₂.HCl.0.1 H₂ O Calcd: C 58.85, H 4.98, N 2.64 Found: C58.48, H 5.01, N 2.50 37

C₂₇H₂₆Cl₂F₂O₃S Calcd: C 60.11, H 4.86 Found: C 60.27, H 4.73 38

C₂₇H₂₆Cl₂F₂O₄S Calcd: C 58.38, H 4.72 Found: C 58.25, H 4.83 39

C₂₇H₂₆Cl₂F₂O₅S.0.4 H₂O Calcd: C 56.04, H 4.67, N 5.54 Found: C 56.01, H4.57, N 5.02

1. A compound selected from

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition for the inhibition of cytosolic phospholipase A₂ comprisinga therapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.